Heterocyclic compounds and their use as angiotensin antagonists

ABSTRACT

r salt thereof show a strong angiotensin II antagonistic activity and hypotensive action and CNS activity, and are useful as therapeutic agents of circulatory diseases such as hypertensive diseases and heart diseases (e.g. hypercardia, heart failure, cardiac infarction), strokes, cerebral apoplexy, nephritis, atherosclerosis, Alzheimer&#39;s disease, senile dementia, etc.

This application is a division of Ser. No. 08/291,435 filed Aug. 16,1994 now U.S. Pat. No. 5,583,141, which is a division of Ser. No.08/080,259 filed Jun. 23, 1993 now U.S. Pat. No. 5,354,766, which is adivision of Ser. No. 07/904,452 filed Jun. 25, 1992 now U.S. Pat. No.5,243,054.

FIELD OF THE INVENTION

This invention relates to novel heterocyclic compounds having excellentpharmacological actions and intermediates for the synthesis thereof.

More specifically, the present invention relates to compounds of thegeneral formula ##STR2## wherein R¹ is an optionally substitutedhydrocarbon residue which is optionally bonded through a hetero-atom; R²is an optionally substituted 5-7 membered heterocyclic residue having,as a group capable of constituting the ring, a carbonyl group, athiocarbonyl group, an optionally oxidized sulfur atom or a groupconvertible into them; X is a direct bond or a spacer having an atomiclength of two or less between the ring Y and the ring W; W and Y areindependently an optionally substituted aromatic hydrocarbon residueoptionally containing a hetero-atom or an optionally substitutedheterocyclic residue; n is an integer of 1 or 2; a and b forming theheterocyclic residue are independently one or two optionally substitutedcarbon or hetero atoms; c is an optionally substituted carbon or heteroatom; and, in the group of the formula ##STR3## substituents on adjacenttwo atoms forming the ring are optionally bonded to each other to form a5-6 membered ring together with the two atoms forming the ring! or asalt thereof.

BACKGROUND OF THE INVENTION

The renin-angiotensin system is involved in the homeostatic function tocontrol systemic blood pressure, the volume of body fluid, balance amongthe electrolytes, etc., associated with the aldosterone system. Therelationship between the renin-angiotensin system and hypertension hasbeen clarified by the development of angiotensin II (AIl) convertingenzyme inhibitors (ACE inhibitor) which counteract angiotensin II withits strong vasoconstrictive action. Since angiotensin II constrictsblood vessel to elevate blood pressure via the angiotensin II receptorson the cellular membranes, angiotensin II antagonists, like the ACEinhibitors, can be used for treating hypertension caused by angiotensin.It has been reported that a number of angiotensin II analogues such assaralasin, Sar¹, Ile⁸ !AII and the like possess potent angiotensin IIantagonist activity. It has, however, been reported that, when peptideantagonists are administered non-orally, their actions are not prolongedand, when administered orally, they are ineffective M. A. Ondetti and D.W. Cushman, Annual Reports in Medicinal Chemistry, 13, 82-91 (1978)!.

On the other hand, for solving the problems observed in these peptideangiotensin II antagonists, studies on non-peptide angiotensin IIantagonists have been developed. In the earliest studies in this field,imidazole derivatives having angiotensin II antagonist activity havebeen disclosed in JPA S56(1981)-71073, S56(1981)-71074, S57(1982)-98270and S58(1983)-157768, U.S. Pat. No. 4,355,040 and 4,340,598, etc. Later,improved imidazole derivatives are disclosed in EP-0253310, EP-0291969,EP-0324377, EP-403158, WO-9100277, JPA S63(1988)-23868 and JPAH1(1989)-117876; pyrrole, pyrazole and triazole derivatives inEP-0323841, EP-0409332 and JPA H1(1989)-287071; benzimidazolederivatives in U.S. Pat. No. 4,880,304, EP-0392317, EP-0399732,EP-0400835 and JPA H3(1991)-63264; azaindene derivatives in EP-0399731;pyrimidone derivatives in EP-0407342; and quinazolinone derivatives inEP-0411766; as angiotensin II antagonists.

However, in order to become a therapeutically useful drug, angiotensinII antagonists are required to have a strong and long-lastingangiotensin II antagonistic action by oral administration. As shown inso far known literature references, the preferable angiotensin IIantagonist is considered to have an acid group, for example, tetrazolegroup or carboxyl group on the biphenyl side chain, especially tetrazolegroup as the most preferable one. Clinical tests of compounds having thetetrazole group for anti-hypertension agents are being conducted Y.Christen, B. Waeber, J. Nussberger, R. J. Lee, P. B. M. W. M.Timmermans, and H. R. Brunner, Am. J. Hypertens., 4, 350S (1991)!.However, compounds having tetrazole ring and azide compounds to be usedfor synthesizing them have been known as involving a danger ofexplosion, which becomes a serious problem to the large scalepreparation and production.

OBJECT OF THE INVENTION

The present invention is to provide a novel compound having aheterocyclic residue substitutable for the tetrazole or carboxylic groupwhich has strong angiotensin II antagonistic action andanti-hypertensive action when administered orally and which becomes atherapeutically useful drug.

The present inventors considered that compounds blockingrenin-angiotensin system as well as being clinically useful for thetreatment of circulatory diseases such as hypertensive diseases, heartdiseases (hypercardia, heart failure, cardiac infarction, etc.),cerebral apoplexy, nephritis, atherosclerosis, etc. are required to havepotent angiotensin II receptor antagonistic activity and to show astrong and long-lasting angiotensin II antagonistic and hypotensiveaction by oral administration, and they have made extensive andintensive studies on a compound having angiotension II antagonisticactivity for years.

As a result, the present inventors have found that novel heterocycliccompounds (I) have a potent angiotensin II receptor antagonisticactivity as well as strong and long-lasting angiotensin II antagonisticand anti-hypertensive actions by oral administration.

SUMMARY OF THE INVENTION

More specifically, the present invention relates to (1) a compound ofthe formula ##STR4## wherein R¹ is an optionally substituted hydrocarbonresidue which is optionally bonded through a hetero-atom; R² is anoptionally substituted 5-7 membered heterocyclic residue having, as agroup capable of constituting the ring, a carbonyl group, a thiocarbonylgroup, an optionally oxidized sulfur atom or a group convertible intothem; X is a direct bond or a spacer having an atomic length of two orless between the ring Y and the ring W; W and Y are independently anoptionally substituted aromatic hydrocarbon residue optionallycontaining a hetero-atom or an optionally substituted heterocyclicresidue; n is an integer of 1 or 2; a and b forming the heterocyclicresidue are independently one or two optionally substituted carbon orhetero atoms; c is an optionally substituted carbon or hetero atom; and,in the group of the formula ##STR5## substituents on adjacent two atomsforming the ring are optionally bonded to each other to form a 5-6membered ring together with the two atoms forming the ring! or a saltthereof, more preferably, (2) a compound of the formula ##STR6## whereinR¹ is an optionally substituted hydrocarbon residue which is optionallybonded through a hetero-atom; R² is an optionally substituted 5-7membered heterocyclic residue having, as a group capable of constitutingthe ring, a carbonyl group, a thiocarbonyl group, an optionally oxidizedsulfur atom or a group convertible into them; X is a direct bond or aspacer having an atomic length of two or less between the ring Y and thering W; W and Y are independently an optionally substituted aromatichydrocarbon residue optionally containing a hetero-atom or an optionallysubstituted heterocyclic residue; n is an integer of 1 or 2; a and bforming the heterocyclic residue are independently one or two optionallysubstituted carbon or hetero atoms; c is an optionally substitutedcarbon or hetero atom; and, when a is an optionally substituted carbonatom, R¹ and a may optionally be bonded to each other to form a group ofthe formula ##STR7## forming a ring! or a slat thereof, or (3) acompound represented of the formula ##STR8## wherein R¹ is an optionallysubstituted hydrocarbon residue which is optionally bonded through ahetero-atom; R² is an optionally substituted 5-7 membered heterocyclicresidue having, as a group capable of constituting the ring, a carbonylgroup, a thiocarbonyl group, an optionally oxidized sulfur atom or agroup convertible into them; X is a direct bond or a spacer having anatomic length of two or less between the ring Y and the ring W; W and Yare independently an optionally substituted aromatic hydrocarbon residueoptionally containing a hetero-atom or an optionally substitutedheterocyclic residue; a and e forming the heterocyclic residue areindependently one or two optionally substituted carbon or hetero atoms;d and f forming the heterocyclic residue are independently oneoptionally substituted carbon or hetero atom; b and c are independentlyone optionally substituted carbon or nitrogen atom; n denotes an integerof 1 or 2; and, when a is an optionally substituted carbon atom, R¹ anda may optionally be bonded to each other to form a group of the formula##STR9## forming a ring! or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Referring to the general formula (I), examples of the hydrocarbonresidue represented by R¹ include alkyl, alkenyl, alkynyl, cycloalkyl,aryl and aralkyl groups. Among them, alkyl, alkenyl and cycloalkylgroups are preferable. The hydrocarbon residue may be bonded to the ringthrough a hetero atom or further substituted with, for example, anoptionally substituted hydrocarbon residue which may be bonded through ahetero-atom.

The alkyl group represented by R¹ is a straight or branched lower alkylgroup having 1 to about 8 carbon atoms, as exemplified by methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,i-pentyl, hexyl, heptyl or octyl.

The alkenyl group represented by R¹ is straight or branched loweralkenyl group having 2 to about 8 carbon atoms, as exemplified by vinyl,propenyl, 2-butenyl, 3-butenyl, isobutenyl or 2-octenyl.

The alkynyl group represented by R¹ is a straight or branched loweralkynyl group having 2 to about 8 carbon atoms, as exemplified byethynyl, 2-propinyl, 2-butynyl, 2-pentynyl or 2-octynyl.

The cycloalkyl group represented by R¹ is a lower cycloalkyl grouphaving 3 to about 6 carbon atoms, as exemplified by cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

The above-mentioned alkyl, alkenyl, alkynyl or cycloalkyl group mayoptionally be substituted with, for example, hydroxyl group, anoptionally substituted amino group e.g. amino, N-lower (1-4C)alkylamino, or N,N-di-lower (1-4C)alkylamino!, halogen, a lower (1-4C)alkoxy group or a lower (1-4C) alkylthio group.

The aralkyl group represented by R¹ is, for example, a phenyl-lower(1-4C) alkyl such as benzyl or phenethyl, and the aryl group representedby R¹ is, for example, phenyl.

The above-mentioned aralkyl or aryl group may optionally have, on anoptional position of its benzene ring, for example, halogen (e.g. F, Clor Br), nitro, an optionally substituted amino group e.g. amino,N-lower(1-4C) alkyl amino, or N,N-di-lower(1-4C) alkylamino!,lower(1-4C) alkoxy (e.g. methoxy, or ethoxy), lower(1-4C) alkylthio(e.g. methylthio or ethylthio) or lower(1-4C) alkyl (e.g. methyl orethyl).

Among the above-exemplified groups represented by R¹, optionallysubstituted alkyl or alkenyl groups (e.g. a lower(1-5C) alkyl orlower(2-5C) alkenyl group optionally substituted with hydroxyl group,amino group, halogen or a lower(1-4C) alkoxy group) are preferable.

The above-mentioned R¹ may optionally be bonded through a hetero-atome.g. nitrogen N(R⁹) (R⁹ stands for hydrogen or a lower(1-4C) alkyl!,oxygen or sulfur --S(O)m- (m denotes an integer of 0 to 2)!, etc.!, and,among them, optionally substituted alkyl or alkenyl groups bondedthrough a hetero-atom (e.g. methylamino, ethylamino, propylamino,propenylamino, isopropylamino, allylamino, butylamino, isobutylamino,dimethylamino, methylethylamino, methoxy, ethoxy, propoxy, isopropoxy,propenyloxy, allyloxy, butoxy, isobutoxy, sec-butoxy, t-butoxy,2-butenyloxy, 3-butenyloxy, isobutenyloxy, pentoxy, isopentoxy,hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, allylthio,butylthio, isobutylthio, sec-butylthio, t-butylthio, 2-butenylthio,3-butenylthio, isobutenylthio, pentylthio, isopentylthio, hexylthio,etc.) are preferable.

Examples of optionally substituted aromatic hydrocarbon or heterocyclicresidues optionally containing a hetero-atom, which are represented by Yand W, include aromatic hydrocarbon residues such as phenyl, and 4- to7-membered monocyclic or condensed heterocyclic residues containing oneor more of N, S and 0, for example, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,isothiazolyl, isooxazolyl, benzofuranyl, isobenzofuranyl, indolizinyl,isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl and pteridinyl (preferably phenyl).

The above-mentioned aromatic hydrocarbon or heterocyclic residuesoptionally containing a hetero-atom, which are represented by Y, have asubstituent represented by R² as exemplified by an optionallysubstituted 5- to 7-membered (preferably 5- to 6-membered) monocyclicheterocyclic residue containing one or more of N, S and O (preferablyN-containing heterocyclic residue having hydrogen atom capable of beingprotonated) or a group convertible thereinto. The group represented byR² are shown below: ##STR10## And, besides the case of carbon-carbonlinkage as in the above, a group represented by R² may optionally bebonded with an optionally substituted aromatic hydrocarbon orheterocyclic residue optionally containing a hetero-atom, which isrepresented by Y, in the case of g=--NH-- in the above formula, throughone of the plural number of existing nitrogen atoms.

For example, when R² = ##STR11## specifically ##STR12## represents thatgroup.

Other examples of R² bonded through the nitrogen atom include ##STR13##In the above formulae, g=--CH₂ --, --NR⁹ --, O atom or##STR14## >=Z, >=Z' and >=Z" respectively stand for a carbonyl group, athiocarbonyl group or an optionally oxidized sulfur atom (e.g. S, S(O),and S(0)₂) (preferably a carbonyl or thiocarbonyl group, more preferablya carbonyl group), m denotes an integer of 0, 1 or 2, and R⁹ stands forhydrogen atom or an optionally substituted lower alkyl group!.

Preferable groups represented by R² are, like oxadiazole or thiadiazolering, those having --NH or --OH group as proton-donor and a carbonylgroup, a thiocarbonyl group or sulfinyl group as proton acceptorsimultaneously. And, while the heterocyclic residue represented by R²may optionally form a condensed ring by the linkage of substituents onthe ring, the preferable ones are 5- to 6-membered heterocyclicresidues, more preferably 5-membered ones. Among others, as R², as agroup of the formula: ##STR15## wherein i is --O-- or --S--, jis >═O, >═S or >S(O)m, and m is of the same meaning as defined above! ispreferable. In case where Y is, for example, phenyl, R² may besubstituted on any of the ortho-, meta- or para-positions, preferablythe ortho-position.

And, while the above-mentioned heterocyclic residue (R²) can exist intautomeric forms as shown below, for example, three tautomers, a', b'and c', in ##STR16## When Z=0, g=0 ##STR17## the heterocyclic residuerepresented by the formula ##STR18## includes all of the above-mentioneda', b' and c'. And, the above-mentioned heterocyclic residue (R²) mayoptionally be substituted with the group represented by R¹⁰, as shownbelow. ##STR19##

Examples of the group represented by R¹⁰ mentioned above include groupsrepresented by the formula--CH(R⁴)--OCOR⁵ wherein R⁴ stands forhydrogen, a 1-6C straight-chain or branched lower alkyl group (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, isopentyl, or neopentyl), a 2-6C straight-chain or branchedlower alkenyl group or a 3-8C cycloalkyl group (e.g. cyclopentyl,cyclohexyl or cycloheptyl); R⁵ stands for a 1-6C straight-chain orbranched lower alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl orneopentyl), a 2-6C straight-chain or branched lower alkenyl group, a3-8C cycloalkyl group (e.g. cyclopentyl, cyclohexyl or cycloheptyl), a1-3C lower alkyl group substituted with a 3-8C cycloalkyl group (e.g.cyclopentyl, cyclohexyl or cycloheptyl) or an optionally substitutedaryl group such as phenyl (e.g. benzyl, p-chlorobenzyl, phenethyl,cyclopentylmethyl or cyclohexylmethyl), a 2-3C lower alkenyl groupsubstituted with a 3-8C cycloalkyl or an optionally substituted arylgroup such as phenyl (e.g. a group having alkenyl moiety such as vinyl(e.g. cinnamyl), propenyl, allyl or isopropenyl), an optionallysubstituted aryl group such as phenyl (e.g. phenyl, p-tolyl ornaphthyl), a 1-6C straight-chain or branched lower alkoxy group (e.g.methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, n-pentyloxy, isopentyloxy or neopentyloxy), a 2-8Cstraight-chain or branched lower alkenyloxy group (e.g. allyloxy, orisobutenyloxy), a 3-8C cycloalkyloxy group (e.g. cyclopentyloxy,cyclohexyloxy or cycloheptyloxy), a 1-3C lower alkoxy group substitutedwith a 3-8C cycloalkyl (e.g. cyclopentyl, cyclohexyl, or cycloheptyl) orwith an optionally substituted aryl such as phenyl (e.g. a group havingalkoxy moiety such as methoxy, ethoxy, n-propoxy or isopropoxy, e.g.benzyloxy, phenethyloxy, cyclopentylmethyloxy, or cyclohexylmethyloxy),a 2-3C lower alkenyloxy group substituted with a 3-8 C cycloalkyl (e.g.cyclopentyl, cyclohexyl, or cycloheptyl) or with an optionallysubstituted aryl such as phenyl (e.g. a group having alkenyloxy moietysuch as vinyloxy (e.g. cinnamyloxy), propenyloxy, allyloxy orisopropenyloxy), an aryloxy group including optionally substitutedphenoxy (e.g. phenoxy, p-nitrophenoxy or naphthoxy)!, and an optionallysubstituted alkyl (e.g. lower (1-4C) alkyl) or acyl (e.g. lower (2-5C)alkanoyl or optionally substituted benzoyl). Examples of R¹⁰ includemethyl, ethyl, propyl, t-butyl, methoxymethyl, triphenylmethyl,cyanoethyl, acetyl, propionyl, pivaloyloxymethyl,1-(cyclohexyloxycarbonyloxy)ethyl,5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetoxymethyl,propionyloxymethyl n-butyryloxymethyl, isobutyryloxymethyl,1-(ethoxycarbonyloxy)ethyl, 1-acetyloxy)ethyl, 1-(isobutyryloxy)ethyl,cyclohexylcarbonyloxymethyl, benzoyloxymethyl, cinnamyl, andcyclopentylcarbonyloxymethyl. Such groups may include substituents whichare capable of easily converting into the initial heterocyclic residuerepresented by the formula ##STR20## either chemically or biologicallyi.e. under physiological conditions (for example, an in vivo reactionsuch as oxidation, reduction or hydrolysis catalyzed by in vivo enzymes(what is called prodrug).

As the above-mentioned tautomers of heterocyclic residues (a', b' andc') and the heterocyclic residue (a", b" and c")substituted with R¹⁰ areincluded in the heterocyclic residues represented by the substituent R²in the present invention, so the tautomers and their substitutedcompounds of various heterocyclic residues described in the foregoingare, as a matter of course, included in the substituent R² in thepresent invention. And, the substituent R² may have further substituentsother than those represented by R¹⁰ described above, as exemplified byan optionally substituted alkyl group (e.g. methyl and triphenylmethyl),halogen (e.g. F, Cl and Br), nitro, cyano, lower (1-4C) alkoxy, and anoptionally substituted amino group (e.g. amino, methylamino, anddimethylamino), among others.

The aromatic hydrocarbon residue and the heterocyclic residue optionallycontaining one or more of N, O, and S atom may optionally havesubstituents as exemplified by halogen (e.g. F, Cl and Br), nitro,cyano, lower (1-4C) alkoxy, an optionally substituted amino group (e.g.amino, methylamino and dimethylamino).

X show that the adjacent ring W (e.g. phenylene group) is bonded to thering Y (e.g. phenyl group) directly or through a spacer with an atomicchain of 2 or less (preferably a direct bond). As the spacer, any onecan be exemplified, so long as it is a divalent chain in which thenumber of atoms constituting the straight chain is 1 or 2, and it mayhave a side chain, more specifically, lower (1-4C) alkylene, --CO--,--O--, --S--, --NH--, --CO--NH--, --O--CH₂ --, --S--CH₂ --, and--CH═CH--. n denotes an integer of 1 or 2 (preferably 1).

Among the compounds shown by R², W, X, Y and n described above, thoseshown by the following formulae, for example, are preferable:

among ##STR21## compounds shown by the formula, e.g. ##STR22## arepreferable.

Typical examples of heterocyclic compounds represented by the formula##STR23## are specifically shown as follows. Incidentally, in thefollowing formulae, R¹ is of the same meaning as defined above, and Rstands for the formula: ##STR24##

Examples of compounds shown by the formula (II), as compounds shown byformula, ##STR25## include the following, but are not limited thereto:##STR26## wherein h is >CH₂, >═O, >═S, >S--(O)_(m), --NR⁹ --and --O--,and m and R⁹ is defined as above; etc., or as compounds shown by formula##STR27## wherein A stands for an optionally substituted aromatichydrocarbon residue, optionally containing a hetero-atom, orheterocyclic residue (preferably aromatic hydrocarbon residue such asphenyl), h and h' each shows

    >CH.sub.2, >═O, >═S, >S--(O).sub.m, --NR.sup.9 -- and --O--

and, m and R⁹ are of the same meaning as defined above! are exemplified.These examples may further include the following: formula the ##STR28##may stand fur a heterocyclic ring, and tricyclic heterocyclic compoundsas shown below ##STR29## wherein R and h are of the same meaning asdefined above, and R^(1a) stands for an optionally substitutedhydrocarbon residue! or bicyclic heterocyclic compounds ##STR30##wherein R, b and c are of the same meaning as defined above, R^(1a)stands for an optionally substituted hydrocarbon residue and h" standsfor --O-- or --S--!.

The heterocyclic compound represented by the above-mentioned formulaII^(b) may optionally be substituted with, besides the groupsrepresented by R, R¹ and R^(1a), a group represented by R³ capable offorming an anion or a group convertible thereinto. The substitutionposition of R³ is on the ring adjacent to the ring to which R is bonded,preferably the position adjacent to R (position of f atom).

Examples of the group R³ capable of forming anion or a group convertiblethereinto include optionally esterified or amidated carboxyl,tetrazolyl, trifluoromethanesulfonic acid amide (--NHSO₂ CF₃),phosphoric acid and sulfonic acid. These groups may optionally beprotected by an optionally substituted lower alkyl group or acyl group,and may be any one as long as they are capable of forming anion underbiological or physiological conditions (for example, an in vivo reactionsuch as oxidation, reduction or hydrolysis by in vivo enzymes) orchemically.

Examples of optionally esterified or amidated carboxyl represented by R³include groups represented by the formula --CO--D wherein D stands forhydroxyl group, optionally substituted amino (e.g. amino, N-lower (1-4C)alkylamino, and N,N-di-lower (1-4C) alkylamino) or optionallysubstituted alkoxy {e.g. a lower (1-6C) alkoxy group, whose alkyl moietyis optionally substituted with hydroxyl group, optionally substitutedamino (e.g. amino, dimethylamino, diethylamino, piperidino andmorpholino), halogen, lower (1-6C)alkoxy, lower (1-6C) alkylthio oroptionally substituted dioxolenyl (e.g.5-methyl-2-oxo-1,3-dioxolen-4-yl), or groups represented by the formula--O--CH(R⁴)--OCOR₅ wherein R⁴ stands for hydrogen, a 1-6C straight-chainor branched lower alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and neopentyl), a 2-6Cstraight-chain or branched lower alkenyl group or a 3-8C cycloalkylgroup (e.g. cyclopentyl, cyclohexyl and cycloheptyl), and R⁵ stands fora 1-6C straight-chain or branched lower alkyl group (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyland neopentyl), a 2-6C straight-chain or branched lower alkenyl group, a3-8C cycloallyl group (e.g. cyclopentyl, cyclohexyl and cycloheptyl), a1-3C lower alkyl group substituted with 3-8C cycloalkyl (e.g.cyclopentyl, cyclohexyl and cycloheptyl) or an optionally substitutedaryl group such as phenyl (e.g. benzyl, p-chlorobenzyl, phenethyl,cyclopentylmethyl and cyclohexylmethyl), a 2-3C lower alkenyl groupoptionally substituted with 3-8C cycloalkyl or an optionally substitutedaryl group such as phenyl (e.g. cinnamyl, etc. having alkenyl moietysuch as vinyl, propenyl, allyl and isopropenyl), an aryl group such asoptionally substituted phenyl (e.g. phenyl, p-tolyl and naphthyl), a1-6C straight-chain or branched lower alkoxy group (e.g. methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,n-pentyloxy, isopentyloxy and neopentyloxy), a 2-8C straight-chain orbranched lower alkenyloxy group (e.g. allyloxy and isobutenyloxy), a3-8C cycloallyloxy group (e.g. cyclopentyloxy, cyclohexyloxy, andcycloheptyloxy), a 1-3C lower lower alkoxy group substituted with 3-8Ccycloalkyl (e.g. cyclopentyl, cyclohexyl and cycloheptyl) or an arylgroup such as optionally substituted phenyl (e.g. benzyloxy,phenethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy having alkoxymoiety such as methoxy, ethoxy, n-propoxy and isopropoxy), a 2-3C loweralkenyloxy group substituted with 3-8C cycloalkyl (e.g. cyclopentyl,cyclohexyl and cycloheptyl) or an aryl group such as optionallysubstituted phenyl (e.g. cinnamyloxy having an alkenyloxy moiety such asvinyloxy, propenyloxy, allyloxy and isopropenyloxy) and an aryloxy groupsuch as optionally substituted phenoxy (e.g. phenoxy, p-nitrophenoxy andnaphthoxy)!}!. And, examples of the substituent represented by R³ mayalso include a group capable of forming anion or a group convertiblethereinto (e.g. tetrazolyl, trifluoromethanesulfonic acid amide,phosphoric acid or sulfonic acid optionally protected with alkyl (e.g.a, lower (1-4C) alkyl) or acyl (e.g. lower (2-5C) alkanoyl andoptionally substituted benzoyl).

Examples of the substituent R³ include --COOH and a salt thereof,--COOMe, --COOEt, --COOtBu, --COOPr, pivaloyloxymethoxycarbonyl,1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl,5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl,acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl,n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl,1-(ethoxycarbonyloxy)ethoxycarbonyl, 1-(acetyloxy)ethoxycarbonyl,1-(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl,benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl andcyclopentylcarbonyloxymethoxycarbonyl. As such groups as above, any onecapable of forming anion (e.g. COO⁻ and its derivatives) or a groupconvertible thereinto under biological or physiological conditions (e.g.in vivo reaction such as oxidation, reduction or hydrolysis catalyzed byin vivo enzymes) or chemically is mentioned. R³ may be carboxyl or aprodrug thereof. R³ may also be groups convertible into anion in vivo,for example, biologically or chemically.

And, a compound, in which R³ is a group capable of forming anion or agroup convertible thereinto (e.g. optionally protected carboxyl group,tetrazolyl group, carboaldehyde group, and hydroxymethyl group; andcyano group) chemically (e.g. oxidation, reduction or hydrolysis), isuseful as a synthetic intermediate.

Among the groups described as R³, preferable ones include carboxyl,esterified carboxyl (e.g. methyl ester, ethyl ester or an ester formedby bonding of a group represented by the above-mentioned formula--O--CH(R⁴)--OCOR⁵ to carbonyl) and optionally protected tetrazolyl,carbaldehyde and hydroxymethyl.

The heterocyclic compound represented by the formula II may optionallyhave; besides the groups represented by R, R¹, R^(1a) and R³, furthersubstituents as exemplified by halogen (e.g. F, Cl and Br), nitro,cyano, an optionally substituted amino group e.g. amino, N-lower (1-4C)alkylamino (e.g. methylamino), N,N-di-lower (1-4C) alkylamino (e.g.dimethylamino), N-arylamino (e.g. phenylamino), alicyclic amino (e.g.morpholino, piperidino, piperazino and N-phenylpiperazino)!, groupsrepresented by the formula--U--R⁶ wherein U stands for a bond, --O--,--S-- or --CO--, and R⁶ stands for hydrogen, an optionally substitutedlower alkyl group (e.g. lower (1-4C) alkyl optionally substituted withhydroxyl group, an optionally substituted amino group (e.g. amino),halogen, nitro, cyano or a lower (1-4C) alkoxy group!, groupsrepresented by the formula --(CH₂)₁ --CO--D' wherein D' stands forhydrogen, hydroxyl group, optionally substituted amino (e.g. amino,N-lower (1-4C) alkylamino and N-N-di-lower (1-4C) alkylamino), oroptionally substituted alkoxy (e.g. a lower (1-6C) alkoxy group whosealkyl moiety is optionally substituted with hydroxyl group, optionallysubstituted amino (e.g. amino, dimethylamino, diethylamino, piperidinoand morpholino), halogen, lower (1-6C) alkoxy, lower (1-6C) alkylthio,or optionally substituted dioxolenyl (e.g.5-methyl-2-oxo-1,3-dioxolen-4-yl) or groups represented by theformula--OCH(R⁷)OCOR⁸ wherein R⁷ stands for hydrogen, 1-6Cstraight-chain or branched lower alkyl group (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl andneopentyl) or a 5-7C cycloalkyl group (cyclopentyl cyclohexyl andcycloheptyl), and R⁸ stands for a 1-6C straight-chain or branched loweralkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl and neopentyl), a 2-8C loweralkenyl group (vinyl, propenyl allyl and isopropenyl), a 5-7C cycloalkylgroup (e.g. cyclopentyl cyclohexyl and cycloheptyl), a 1-3C lower alkylgroup substituted with a 5-7C cycloalkyl group (e.g. cyclopentyl,cyclohexyl and cycloheptyl) or an aryl group such as phenyl (e.g.benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl andcyclohexylmethyl), a 2-3C lower alkenyl group substituted with 5-7Ccycloalkyl (e.g. cyclopentyl, cyclohexyl and cycloheptyl) or an arylgroup such as phenyl (e.g. cinnamyl having an alkenyl moiety such asvinyl, propenyl, allyl or isopropenyl), an optionally substituted arylgroup such as phenyl (e.g. phenyl, p-tolyl and naphthyl), a 1-6Cstraight-chain or branched lower alkoxy group (e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy,n-pentyloxy, isopentyloxy and neopentyloxy), a 2-8C straight-chain orbranched lower alkenyloxy group (e.g. allyloxy and isobutenyloxy), a5-7C cycloalkyloxy group (e.g. cyclopentyloxy, cyclohexyloxy andcycloheptyloxy), a 1-3C lower alkoxy group substituted with 5-7Ccycloalkyl (e.g. cyclopentyl, cyclohexyl and cycloheptyl) or an arylgroup such as optionally substituted phenyl (e.g. benzyloxy,phenethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy having alkoxymoiety such as methoxy, ethoxy, n-propoxy and isopropoxy), a 2-3Calkenyloxy group substituted with 5-7C cycloalkyl (e.g. cyclopentyl,cyclohexyl and cycloheptyl) or an optionally substituted aryl group suchas phenyl (e.g. cinnamyloxy having alkenyloxy moiety such as vinyloxy,propenyloxy, allyloxy and isopropenyloxy) and an aryloxy group such asoptionally substituted phenoxy (e.g. phenoxy, p-nitrophenoxy andnaphthoxy)!, and 1 denotes 0 or 1! or tetrazolyl,trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid,each optionally protected with alkyl (e.g. lower (1-4C) alkyl) or acyl(e.g. lower (2-5C) alkanoyl and optionally substituted benzoyl).

One or two of these substituents may optionally be substitutedsimultaneously on optional positions of the ring. When two or more ofthese substituents exist, (preferably the case where two substituentsexist on two ring-forming atoms adjacent to each other in a, b and c forring-forming groups), they may be bonded to each other to form a 5- to6-membered optionally substituted aromatic hydrocarbon residue or aheterocyclic residue (preferably an aromatic ring such as phenyl)optionally containing hetero atom, taken together with the tworing-forming atoms. These rings may further substituted with any of theabove-described substituents.

Among the compounds shown by formula ##STR31## as condensed heterocyclicring shown by formula ##STR32## preferable examples are ##STR33##wherein R, R¹, R³ and h are of the same meaning as defined above! and asheterocyclic ring represented by the formula ##STR34## wherein R, R¹, R³and R⁹ are of the same meaning as defined above! are preferable.

Among the compounds represented by the above-mentioned formula (I^(a)),preferable ones are represented by the formula ##STR35## (wherein R¹stands for optionally substituted lower (1-5C) alkyl which may be bondedthrough a hetero-atom (e.g. O, N(H) and S) (preferably lower (2-4C)alkyl), R² stands for oxadiazole or thiadiazole optionally protectedwith optionally substituted lower (1-4C) alkyl (e.g. methyl,triphenylmethyl, methoxymethyl, acetyloxymethyl,methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,cyclohexyloxycarbonyloxyethyl and pivaloyloxymethyl) or an acyl (e.g.lower (2-5C alkanoyl and benzoyl), R³ stands for groups represented bythe formula --CO--D" wherein D" stands for hydroxyl group, amino,N-lower (1-4C) alkylamino, N,N-di-lower (1-4C) alkylamino or lower(1-4C) alkoxy whose alkyl moiety may optionally be substituted withhydroxyl group, amino, halogen, lower (2-6C) alkanoyloxy (e.g. acetyloxyand pivaloyloxy), 1-lower (1-6C) alkoxycarbonyl (e.g.methoxycarbonyloxy, ethoxycarbonyloxy and cyclohexyloxycarbonyloxy) orlower (1-4C) alkoxy! or tetrazolyl optionally protected with lower(1-4C) alkyl or acyl group (e.g. lower (2-5C) alkanoyl and benzoyl), andheterocyclic ring represented by ##STR36## shows ##STR37##

Among the compounds represented by the above-mentioned formula (I^(b)),preferable ones are represented by the formula ##STR38## wherein R¹stands for optionally substituted lower (1-5C) alkyl which may be bondedthrough a hetero-atom (e.g. O, N(H) and S) (preferably lower (2-4C)alkyl), R² stands oxadiazole or thiadiazole optionally protected withoptionally substituted lower (1-4C) alkyl (e.g. methyl, triphenylmethyl,methoxymethyl, acetyloxymethyl, methoxycarbonyloxymethyl,ethoxycarbonyloxymethyl, cyclohexyloxycarbonyloxyethyl andpivaloyloxymethyl) or an acyl (e.g. lower (2-5C alkanoyl and benzoyl),R³ stands for hydrogen, groups represented by the formula --CO--D"wherein D"stands for hydroxyl group, amino, N-lower (1-4C) alkylamino,N,N-di-lower (1-4C) alkylamino or lower (1-4C) alkoxy whose alkyl moietymay optionally be substituted with hydroxyl group, amino, halogen, lower(2-6C) alkanoyloxy (e.g. acetyloxy and pivaloyloxy), 1-lower (1-6C)alkoxycarbonyl (e.g. methoxycarbonyloxy, ethoxycarbonyloxy andcyclohexyloxycarbonyloxy) or lower (1-4C) alkoxy! or tetrazolyloptionally protected with lower (1-4C) alkyl or acyl group (e.g. lower(2-5C) alkanoyl and benzoyl), and the condensed heterocyclic ringrepresented by ##STR39## shows ##STR40## which may be furthersubstituted with the above-mentioned substituents in addition to groupsof R, R¹ and R³ !. As a compound of the formula (I^(b)), compoundshaving benzimidazole, thienoimidazole or imidazopyridine structure arepreferable (more preferably, benzimidazole or thienoimidazole). And,compounds represented by the formula (I^(a)) or (I^(b)). wherein R² ishydroxyiminocarboxamide (--C(NH₂)═N--OH) are useful intermediates forsynthesizing compounds of the formula (I^(a)) or (I^(b)) wherein R² isoxadiazole or thiadiazole.

Production Method

The compounds represented by the above-mentioned general formula (I), or(I^(a)) or (I^(b)) can be produced by, for example, methods asillustrated below.

Reaction (a) ##STR41## wherein R¹, R², W, X, Y, a, b, c and n are of thesame meaning as defined above, and L stands for a halogen atom!.

The above-illustrated reaction (a) is alkylation using an alkylatingagent in the presence of a base.

The alkylation is conducted, employing approximately 1 to 3 moles eachof the base and the alkylating agent relative to one mole of thecompound (III), usually in a solvent such as dimethylformamide,dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone or ethylmethyl ketone.

Examples of the base include sodium hydride, potassium t-butoxide,potassium carbonate and sodium carbonate.

As the alkylating agent, use is made of, for example, substitutedhalides (e.g. chlorides, bromides and iodides) and substituted sulfonicacid esters (e.g. p-toluenesulfonic acid ester).

While the reaction conditions vary with the combination of the base andthe alkylating agent then employed, it is preferable to conduct thereaction usually at 0° C. to room temperature for about 1-10 hours.

In the alkylation, a mixture of regioisomers is obtained depending onthe position of the N atom. While the production ratio of thesecompounds varies with the reaction conditions then employed and thesubstituents on the heterocyclic ring, these compounds can be obtainedeasily as pure products respectively by conventional isolation andpurification means (e.g. recrystallization and column chromatography).

Reaction (b) ##STR42## wherein R¹, W, X, Y, a, b, c and n are of thesame meaning as defined above!.

The above-mentioned reaction (b) is to obtain the oxadiazole compound(Ic) by converting the cyano compound (Ia) into the amidoxime (Ib)followed by closing the ring.

The reaction for obtaining the compound (Ib) is conducted by usingapproximately 2 to 10 moles of hydroxylamine relative to 1 mole of thecompound. (Ia) usually in an organic solvent.

Examples of the solvent include amides (e.g. dimethylformamide anddimethylacetamide), sulfoxides (e.g. dimethyl sulfoxide), alcohols (e.g.methanol and ethanol), ethers (e.g. dioxane and tetrahydrofuran) andhalogenated hydrocarbons (e.g. methylene chloride and chloroform).

When hydroxylamine is employed, the reaction is conducted in thepresence of a suitable base (e.g. potassium carbonate, sodium carbonate,sodium hydroxide, triethylamine, sodium methanolate, sodium ethanolateand sodium hydride) of about equimolar amount, in the case of using aninorganic acid salt (e.g. hydroxylamine hydrochloride or hydroxylaminesulfate) or an organic acid salt (e.g. hydroxylamine oxalate). While thereaction conditions vary with the reagent or solvent then employed, thereaction is preferably conducted at about 50° C. to about 100° C. forabout 2-10 hours, after the hydroxylamine hydrochloride is treated withsodium methoxide in dimethyl sulfoxide.

The thus-obtained amidoxime (Ib) is allowed to react with chloroformate(e.g. methyl ester and ethyl ester) in a conventional organic solvent(e.g. chloroform, methylene chloride, dioxane, tetrahydrofuran,acetonitrile and pyridine) in the presence of a base (e.g.triethylamine, pyridine, potassium carbonate and sodium carbonate) togive an o-acyl compound.

Preferably, the reaction is usually conducted by using 2-5 moles ofethyl chloroformate relative to one mole of the amidoxime (Ib) in thepresence of about 2 to 5 moles of triethylamine in tetrahydrofuran at 0°C. to room temperatures for about 1 to 5 hours.

By heating the thus-obtained o-acyl amidoxime in a conventional organicsolvent, the cyclized compound (Ic) is easily obtained.

Examples of the solvent include aromatic hydrocarbons (e.g. benzene,toluene and xylene), ethers (e.g. dioxane and tetrahydrofuran) andhalogenated hydrocarbons (e.g. dichloroethane and chloroform).Preferably, oxadiazole is prepared by heating the o-acyl amidoximecompound for about 1 to 3 hours under reflux in xylene.

Reaction (c) ##STR43##

The reaction (c) is to obtain oxadiazolone (Id) by hydrolyzing thecompound (V) produced by alkylation of the compound (III) with thealkylating agent obtained in the reaction (m).

Examples of the organic solvent include ethers (e.g. dioxane andtetrahydrofuran) and alcohols (e.g. methanol and ethanol).

As the alkali, mention is made of sodium hydroxide, potassium hydroxideand lithium hydroxide.

Preferably, the compound (V) is reacted at 0° C. to room temperaturesfor about 0.5 to 2 hours with about 2-10 moles of 0.5 to 1N sodiumhydroxide.

Reaction (d) ##STR44##

The reaction (d) is to obtain the alcohol compound (Ie) by reducing thealdehyde compound (If).

The reaction is conducted by using about 2 to 5 moles of a reducingagent relative to one mole of the compound (Ie) usually in ethers (e.g.tetrahydrofuran and dioxane) or alcohols (e.g. methanol and ethanol).

As the reducing agent, mention is made of metallic hydrogen complexessuch as sodium borohydride.

Preferably, the reaction is carried out by adding a reducing agent to asolution of the compound (Ie) in methanol at 0° C. to room temperatureand allowing to proceed for about 0.5 to 2 hours.

Reaction (e) ##STR45## wherein R¹, R², W, X, Y. a, b, c, d, e, f and nare of the same meaning as defined above, and L stands for halogenatom!.

The above reaction (e) is to conduct alkylation by an alkylating agentin the presence of a base.

The reaction is conducted by using 1 to 3 moles of the base and 1 to 3moles of the alkylating agent relative to 1 mole of the compound (III)usually in a solvent such as dimethylformamide, dimethyl acetamide,dimethyl sulfoxide, acetonitrile, acetone or ethyl methyl ketone.

Examples of the base include sodium hydride, potassium t-butoxide,potassium carbonate and sodium carbonate.

As the alkylating agent, use is made of substituted halogenides (e.g.chloride, bromide and iodide) and substituted sulfonic acid esters (e.g.p-toluenesulfonic acid ester).

While the reaction conditions vary depending on combination of the basewith the alkylating agent then employed, it is preferable to conduct thereaction usually at 0° C. to room temperature for about 1 to 10 hours.

By the said alkylation, a mixture of regioisomers is sometimes obtaineddepending on the position of the N atom to be alkylated. While theproduction ratio of the compounds varies with the reaction conditionsthen employed and the substituents on the heterocyclic ring, thecompound (I^(b)) can be easily obtained as pure product by subjectingthe mixture to conventional isolation and purification means (e.g.recrystallization and column chromatography).

Reaction (f) ##STR46## wherein R¹, W, X, Y, a, b, c, d, e, f and n areof the same meaning as defined above!.

The reaction (f) is to obtain the oxadiazole compound (I^(b) C) byconverting the cyano compound (I^(b) a) to the amidoxime (I^(b) b),followed by cyclization.

The reaction for obtaining the compound (I^(b) b) is conducted by usinghydroxylamine in an amount of about 2 to 10 moles relative to 1 mole ofthe compound (I^(b) a) in a conventional organic solvent.

Examples of the solvent include amides (e.g. dimethylformamide anddimethylacetamide), sulfoxides (e.g. dimethyl sulfoxide), alcohols (e.g.methanol and ethanol), ethers (e.g. dioxane and tetrahydrofuran) andhalogenated hydrocarbons (e.g. methylene chloride and chloroform).

When hydroxylamine is employed, the reaction is conducted in thepresence of a suitable base (e.g. potassium carbonate, sodium carbonate,sodium hydroxide, triethylamine, sodium methanolate, sodium ethanolateand sodium hydride) of about equimolar amount, in the case of using aninorganic acid salt (e.g. hydroxylamine hydrochloride or hydroxylaminesulfate) or an organic acid salt (e.g. hydroxylamine oxalate). While thereaction conditions vary with the reagent or solvent then employed, thereaction is preferably conducted at about 50° C. to about 100° C. forabout 2 to 10 hours, after the hydroxylamine hydrochloride is treatedwith sodium methoxide in dimethyl sulfoxide.

The thus-obtained amidoxime (I^(b) b) is allowed to react withchloroformic acid ester (e.g. methyl ester and ethyl ester) in aconventional organic solvent (e.g. chloroform, methylene chloride,dioxane, tetrahydrofuran, acetonitrile and pyridine) in the presence ofa base (e.g. triethylamine, pyridine, potassium carbonate and sodiumcarbonate) to give an o-acyl compound.

Preferably, the reaction is usually conducted by using 2-5 moles ofethyl chloroformate relative to one mole of the amidoxime compound(I^(b) b) in the presence of about 2 to 5 moles of triethylamine intetrahydrofuran at 0° C. to room temperatures for about 1 to 5 hours.

By heating the thus-obtained o-acyl amidoxime compound in a conventionalorganic solvent, the cyclized compound (Ic) is easily obtained.

Examples of the solvent include aromatic hydrocarbons (e.g. benzene,toluene and xylene), ethers (e.g. dioxane and tetrahydrofuran) andhalogenated hydrocarbons (e.g. dichloroethane and chloroform).Preferable reaction conditions are heating the o-acyl amidoxime compoundfor about 1 to 3 hours under reflux in xylene.

Reaction (g) ##STR47## wherein R¹, R², R⁹, W, X, Y, a, b, c, d, e and nare of the same meaning as defined above!.

The reaction (g) is to obtain the carboxylic acid (I^(b) e) by alkalihydrolysis of the ester compound (I^(b) d).

This reaction is conducted by using alkali in an amount of about 1 to 3moles relative to one mole of the compound (I^(b) d) usually in asolvent such as aqueous alcohols (e.g. methanol, ethanol and methylcellosolve).

Examples of the alkali include lithium hydroxide, sodium hydroxide andpotassium hydroxide.

The reaction is conducted at room temperature to about 100° C. for about1 to 10 hours, preferably at about the boiling point of the solvent forabout 3 to 5 hours.

Reaction (h) ##STR48## wherein R¹, R², W, X, Y, a, b, c, d, e and n areof the same meaning as defined above, and R¹¹ stands for optionallysubstituted alkyl group shown by the afore-mentioned R¹⁰ !.

The above reaction (h) is alkylation by an alkylating agent in thepresence of a base.

The alkylation is conducted by using 1 to 3 moles of the base and about1 to 3 moles of the alkylating agent relative to 1 mole of the compound(I^(b) e) usually in a solvent such as dimethylformamide,dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone and ethylmethyl ketone.

Examples of the base include sodium hydride, potassium t-butoxide,potassium carbonate and sodium carbonate.

Examples of the alkylating agent include substituted halides (e.g.chloride, bromide and iodide) and substituted sulfonic acid esters (e.g.p-toluenesulfonic acid ester).

While the reaction conditions vary with combinations of the base and thealkylating agent then employed, it is preferable to conduct the reactionat 0° C. to room temperatures for about 1 to 10 hours.

And, when chloride or bromide is employed as the alkylating agent, it ispreferable to add potassium iodide or sodium iodide to the reactionsystem to accelerate the reaction.

Reaction (i) ##STR49## wherein R¹, W, X, Y, a, b, c, d, e, f and n areof the same meaning as defined above!

The reaction (i) is to obtain the oxathiadiazole (I^(b) g) bycyclization of the aldoxime compound (I^(b) b) obtained by the reaction(f).

The compound (I^(b) g) is obtained by cyclizing aldoxime (I^(b) b) withthionyl chloride in a conventional organic solvent (e.g.dichloromethane, chloroform, dioxane and tetrahydrofuran) in thepresence of a base (e.g. pyridine and triethylamine).

It is preferable to conduct the reaction, adding about 2 to 10 moles ofthionyl chloride to the reaction system, under cooling at 0° C. to -30°C., in the presence of about 1 to 3 moles of pyridine to one mole of thealdoxime compound (I^(b) b), using dichloromethane as the solvent, forabout 0.5 to 1 hour.

Reaction (j) ##STR50##

The above reaction (j) is to obtain the diamino derivative (VIII), whichcomprises subjecting the nitro derivative (VII) prepared in accordancewith the procedure described in EP-434038 and EP-459136 to deprotectionby a conventional process, then allowing a reducing agent (e.g.catalytic reduction using Raney nickel or palladium-carbon,iron-hydrochloric acid, ferric chloride -hydrazine, stannic chloride,sodium borohydride-nickel chloride, etc.) to act on the thus deprotectedcompound. Then the diamino derivative (VIII) is allowed to react withcarboxylic acid or a derivative thereof (e.g. ester, acid anhydride oracid halide), ortho-ester, imino ether or imino thioether to causecondensing ring-closure to thereby convert the diamino derivative (VIII)into the compound (IX).

Thus-obtained compound (IX) is allowed to react with about 1 to 2 timesas many moles of triethyloxonium tetrafluoroborate in halogenatedhydrocarbon (e.g. methylene chloride or chloroform) at 0° C. to roomtemperature for about 30 minutes to about 2 hours to give theimino-ether derivative (X) in a good yield.

Then, the imino-ether derivative (X) is allowed to react with 1 to 2times as many moles of chloroformic acid ester (e.g. chloromethylformate or chloroethyl formate) in a conventional organic solvent (e.g.benzene, toluene, methylene chloride, chloroform, dioxane or pyridine)in the presence of about 1 to 2 times as many moles of a base (e.g.2,4,6-trimethylpyridine, triethylamine, dimethylpyridine,methylpyridine, diethylaniline, etc.). More specifically, the reactionis conducted in toluene at 80° to 100° C. for about 1-3 hours to obtainthe N-alkoxycarbonyl derivative (XI) in a good yield.

The thus-obtained acyliminoether derivative (XI) is allowed to reactwith about two times as many moles of hydroxylamine hydrochloride and abase (e.g. sodium methoxide, sodium ethoxide potassium carbonate) inalcohol (e.g. methanol or ethanol) to cause ring-closure. This reactionis conducted preferably at about 50° C. to the boiling point of thesolvent used for about 3-10 hours.

Reaction (k) ##STR51##

The reaction (k) comprises leading the nitrile derivative (XII)synthesized in accordance with the methods disclosed in EP-434038 andEP-459136 to the aldoxime derivative (XIII) obtained by the similarprocedure described in the afore-mentioned reaction (b), followed byallowing the aldoxime derivative (XIII) to react with about 1 to 2 timesas many moles of chloroformic acid ester (e.g. chloromethyl formate orchloroethyl formate) in the presence of about 1 to 2 times as many molesof a base (e.g. triethylamine or pyridine) in a conventionalnon-protomic organic solvent (e.g. benzene, toluene, methylene chloride,chloroform, dioxane or pyridine) in substantially the same manner as inthe afore-mentioned reaction (j). In the case of conducting thisreaction in tetrahydrofuran, the reaction is allowed to proceed at 0° C.to about room temperature to thereby obtain the O-alkoxycarbonylderivative (XV) in a good yield.

The thus-obtained compound (XV) is allowed to react in a conventionalorganic solvent (e.g. methanol, ethanol, ethyl acetate, benzene,acetonitrile, acetone or N,N-dimethylformamide) in the presence of abase (e.g. potassium carbonate, sodium carbonate, sodium hydride,potassium tert-butoxide or 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU)).This reaction is conducted preferably at room temperature to the boilingpoint of the solvent used for about 1-20 hours. When the reaction isallowed to proceed in ethyl acetate using DBU at about 50° to 80° C. forabout 1-2 hours, the ring-closed derivative (I^(b) c) can be obtained ina good yield.

Reaction (1) ##STR52##

The reaction (1) is to obtain the thiadiazole derivative (I^(b) c) bysubjecting the aldoxime (I^(b) b) to ring-closure reaction.

This reaction is conducted in a conventional organic solvent using about1 to 2 moles of 1,1'-thiocarbonyl diimidazole relative to 1 mole of thecompound (I^(b) b).

As the solvent, use is made of, for example, ethers (e.g. dioxane ortetrahydrofuran) or halogenated hydrocarbons (e.g. methylene chloride orchloroform).

The reaction is preferably conducted by dissolving the compound (I^(b)b) in the above-mentioned solvent, adding to the solution1,1'-thiocarbonyl dimidazole while stirring at 0° C. to roomtemperature, followed by stirring with silica gel in a mixture ofmethanol and chloroform for about 30 minutes to 2 hours at roomtemperature.

The reaction products obtained as above by the reactions (a) to (1) canbe easily isolated by conventional isolation and purification methods,for example, column chromatography and recrystallization.

Incidentally, these compounds (I) can be converted, by conventionalmethods, to salts with physiologically acceptable acids or bases. Thesesalts include, for example, salts with an inorganic acid such ashydrochloric acid, sulfuric acid and nitric acid and, depending on thecompounds, salts with an organic acid such as acetic acid, nitric acid,succinic acid and maleic acid, salts with an alkali metal such as sodiumand potassium, and salts with an alkaline earth metal such as calcium.

The starting compounds can be synthesized by the methods described asfollows.

Reaction (m) ##STR53## wherein L has the same meaning as defined above!

The reaction (m) is to obtain the compound (IVd), by converting thecyano compound (IVa) to the aldoxime compound (IVb) under substantiallythe same reaction conditions as in the reaction (b), then subjecting thealdoxime compound (IVb) to cyclization to give the oxadiazole compound(IVc), followed by subjecting the oxadiazole compound (IVc) tohalogenization.

A preferable example of the reaction is as follows.

The aldoxime compound (IVb) obtained from the compound (IVa) by thesimilar procedure described in the reaction (f) is allowed to react withabout 1 to 10 moles of trichloroacetic anhydride or hexachloroacetonerelative to 1 mole of the aldoxime (IVb) in accordance with the methoddescribed in the literature reference F. Eloy, et al., Helv. Chim. Acta,49, 1430(1966)! to give the oxadiazole compound (IVc), then the compound(IVc) thus obtained is allowed to react with a halogenating agent (e.g.N-bromosuccinimide and N-bromoacetamide) (molar ratio=1: about 1 to 1.5)in halogenated hydrocarbon (e.g. carbon tetrachloride) at 50° C. to theboiling point of the solvent for about 1-3 hours, in the presence of acatalytic amount of an initiator (e.g. benzoyl peroxide andazobisisobutyronitrile). This reaction may be carried out underirradiation of light.

Reaction (n) ##STR54## wherein R¹³ stands for the optionally substitutedalkyl group shown by the above-mentioned R¹⁰ (e.g. triphenyl methyl,methoxy methyl and cyanoethyl) or t-butyldimethyl silyl group; and L isof the same meaning as defined above!.

The reaction (n) is to obtain the oxadiazole compound (IVh), whichcomprises leading carboxylic acid (IVe) to acyl isothiocyanate by aconventional method, allowing the latter to react with alcohol to givethe carbonyl thiocarbamate (IVf), subjecting the compound (IVf) tomethylation to give carbonate (IVg), then allowing the compound (IVg) toreact with hydroxylamine, followed by cyclization under heating.

In the reaction for obtaining carbonyl thiocarbamate (IVf) fromcarboxylic acid (IVe), the compound (IVe) is allowed to react with ahalogenating agent (e.g. thionyl chloride) (molar ratio=1: about 2 to 5)in halogenated hydrocarbon (e.g. chloroform and methylene chloride) forabout 1-5 hours at about 50° C. to the boiling point of the solvent thenemployed. The acid chloride thus obtained is allowed to react with about2-5 moles of thiocyanate (e.g. sodium salt and potassium salt) in ether(e.g. dioxane and tetrahydrofuran) at from about 50° C. to the boilingpoint of the solvent then employed for about 1-3 hours to giveisocyanate. It is preferable to subject the isothiocyanate thus obtainedto heating together with about 2-10 moles of alcohol (e.g. methanol andethanol) at about 50° C. to the boiling point of the solvent thenemployed for about 15 minutes to one hour.

In the reaction for obtaining iminomonothio-carbonate (IVg) from thecompound (IVf), it is preferable to allow the compound (IVf) to reactwith methyl iodide (molar ratio=1:1 to 2) in an organic solvent (e.g.methanol, ethanol, dimethylformamide (DMF) and acetonitrile), in thepresence of about 1 to 2 moles, relative to one mole of (IVf), of a base(e.g. NaOMe, Na₂ CO₃ and K₂ CO₃) at room temperature to about 50° C. forabout 10-24 hours.

In the reaction for obtaining the oxadiazole compound (IVh) from thecompound (IVg), it is preferable to allow (IVg) to react withhydroxylamine (molar ratio=1: about 1 to 2) in alcohol (e.g. methanoland ethanol) at room temperature to 50° C. for about 10-20 hours,followed by subjecting the reaction mixture to heating in an organicsolvent (e.g. toluene and benzene) in the presence of about a catalyticamount of an acid (e.g.p-toluenesulfonic acid) at 50° C. to the boilingpoint of the solvent then employed for about 1-3 hours.

In the reaction for obtaining demethylated compound (IVi) from thecompound (IVh), it is preferable to subject an excess amount of pyridinehydrochloride and (IVh) to fuse under nitrogen atmosphere at about 150°C. to 160° C. for about 30 minutes-one hour.

In the reaction for obtaining the compound (IVj) from the compound(IVi), it is preferable to allow the compound (IVi) to react with analkylating agent (e.g. triphenylmethyl chloride, methoxymethyl chlorideand cyanoethyl chloride) (molar ratio=1: about1 to 2) in an organicsolvent (e.g. chloroform, methylene chloride, dioxane, tetrahydrofuranand pyridine) in the presence of about 1 to 2 moles of a base (e.g.potassium carbonate, sodium carbonate, triethylamine and pyridine) at 0°C. to room temperature for about 1-3 hours.

The reaction for obtaining the compound (IVk) by halogenating thecompound (IVj) can be conducted in substantially the same manner as inthe reaction for obtaining the compound (IVd) from the compound (IVc) inthe reaction (m).

Reaction (o) ##STR55## wherein R¹³ and L are of the same meaning asdefined above!

The reaction (o) comprises converting carboxylic acid (IVe) tosemicarbazide (IVm) via hydrazide (IV1) by a conventional manner, thensubjecting (IVm) to dehydrocyclization to give oxadiazolone (IVn),followed by leading (IVn) to the halogeno compound (IVp).

In the reaction for obtaining hydrazide (IV1) from carboxylic acid(IVe), (IVe) is allowed to react with about 2 to 5 moles of ahalogenating agent (e.g. oxalyl chloride and thionyl chloride) in anorganic solvent (e.g. tetrahydrofuran, chloroform and methylenechloride) at room temperature to the boiling point of the solvent thenemployed for about 1-20 hours. In this case, it is preferable to add acatalytic amount of dimethylformamide to accelerate the reaction. Theacid chloride obtained is allowed to react with about 2 to 5 moles ofhydrazine hydrate in an organic solvent (e.g. tetrahydrofuran anddioxane) at room temperature to about 50° C. for about 1-10 hours toobtain compound (IV1). In the reaction for producing semicarbazide (IVm)from the hydrazide (IV1), it is preferable to allow (IVe) to react withabout 2-5 moles of, isocyanate (e.g. sodium or potassium salt) inaqueous solution in the presence of an acid (e.g. hydrochloric acid orsulfuric acid) in an amount equal to that of the isocyanate employed at0° C. to room temperature for about 1-5 hours.

In the reaction for producing oxadiazolone (IVn) from the semicarbazide(IVm), it is preferable to heat (IVm) in an organic solvent (e.g.benzene and xylene) at the boiling point of the solvent for about 5-20hours.

The reaction for producing the halogenated compound (IVp) from theoxadiazolone (IVn) is preferably conducted in a manner similar to thatdescribed in the reaction (n).

Reaction (p) ##STR56## The reaction (p) is to obtain the amide (lVq) insubstantially the same manner as in the reaction (o).

The carboxylic acid (IVe) is allowed to react with about 2-5 mole of ahalogenating agent (e.g. oxalyl chloride or thionyl chloride) in anorganic solvent (e.g. tetrahydrofuran, chloroform or methylene chloride)at room temperature to the boiling point of the solvent used for about1-20 hours. It is preferable to accelerate this reaction by the additionof a catalytic amount of dimethylformamide. The acid halide obtained ispreferably allowed to react with an excess amount of aqueous ammoniumhydroxide in an organic solvent (e.g. tetrahydrofuran or dioxane) at 0°C. to room temperature for about 1-10 hours, so that the amidederivative (IVq) can be obtained in a good yield.

The reaction to obtain the halide (IVr) from the amide derivative (IVq)obtained is preferably conducted in substantially the same manner asshown by the reaction (m) or (n).

The compounds (I) and salts thereof are less toxic, strongly inhibit thevasoconstrictive and hypertensive actions of angiotensin II, exert ahypotensive effect in animals, especially mammals (e.g. human, dog,rabbit and rat), and therefore they are useful as therapeutic agents fornot only hypertension but also circulatory diseases such as heartfailure (hypertrophy of the heart, cardiac insufficiency, cardiacinfarction or the like), cerebral apoplexy and nephropathy. Thecompounds (I) also have CNS activity for treating Alzheimer's diseaseand senile dementia, and anxiolytic and antidepressant properties.

For such therapeutic use as above, the compound (I) and salts thereofcan be administered orally, non-orally, by inhalation, rectally ortopically as pharmaceutical compositions or formulations (e.g. powders,granules, tablets, pills, capsules, injections, syrups, emulsions,elixir, suspensions or solutions), comprising at least one species ofthe compounds of this invention alone or in admixture withpharmaceutically acceptable carriers, adjuvants, vehicles and/ordiluents.

Pharmaceutical compositions can be formulated in accordance withconventional procedures. In the present specification, "non-orally"includes subcutaneous injection, intravenous injection, intramuscularinjection, intraperitoneal injection or instillation. Injectablepreparations, for example, sterile injectable aqueous suspensions or oilsuspensions can be prepared by known procedures in the fields concerned,using a suitable dispersant or wetting agent and suspending agent. Thesterile injections may be in the state of, for example, a solution or asuspension, which is prepared with a non-toxic diluent administrablenon-orally, e.g. an aqueous solution, or with a solvent employable forsterile injection. Examples of usable vehicles or acceptable solventsinclude water, Ringer's solution and an isotonic aqueous salinesolution. Further, a sterile non-volatile oil can usually be employed assolvent or suspending agent. Any non-volatile oil and a fatty acid canbe sued for this purpose, which includes natural, synthetic orsemi-synthetic fatty oil or fatty acid and natural or synthetic orsemi-synthetic mono- or di- or tri-glycerides.

Rectal suppositories can be prepared by mixing the drug with a suitablenon-irritable vehicle, for example, cocoa butter and polyethyleneglycol, which is in the solid state at ordinary temperatures, in theliquid state at temperatures in the intestinal tubes and melts in therectum to release the drug.

As a solid formulation for oral administration, mention is made ofpowders, granules, tablets, pills and capsules as referred to above. Insuch formulations as exemplified above, the active component compoundcan be mixed with at least one additive, for example, sucrose, lactose,cellulose sugar, mannitol, maltitol, dextrin, starch, agar, alginate,chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen,casein, albumin, synthetic or semi-synthetic polymer or glyceride. Theseformulations can contain further additives, for example, an inactivediluent, a lubricant such as magnesium stearate, a preservative such asparaben or sorbic acid, an anti-oxidant such as ascorbic acid,α-tocopherol or cysteine, a disintegrator, a binder, a thickening agent,a buffer, a sweetener, a flavoring agent and a perfuming agent. Tabletsand pills can further be applied with enteric coating. Examples ofliquid preparations for oral administration include pharmaceuticallyacceptable emulsions, syrups, elixirs, suspensions and solution, whichmay contain an inactive diluent, for example, water, which isconventionally employed in the field concerned.

The dose of a specific patient is decided in accordance with the age,body weight, general health conditions, sex, diet, dose interval,administration routes, excretion rate, combinations of drugs andconditions of the diseases then treated, while taking them and any othernecessary factors into consideration.

The dose varies with the diseases to be treated, conditions of suchdiseases, subject patients and administration routes, and it ispreferable that a daily dose of 1 to 50 mg for oral administration or 1to 30 mg for intravenous injection is given once or divided into 2 to 3administrations when used as an agent for the therapy of essentialhypertension of an adult human.

WORKING EXAMPLES!

By the following formulation examples, working examples, experimentalexamples and reference examples, the present invention will beillustrated more concretely, and it is needless to say that they shouldnot be construed as limiting the invention thereto.

Formulation Examples

When the compound (I) of the present invention is used as a therapeuticagent for circulatory disturbances such as hypertension, heart diseases,cerebral apoplexy and nephritis, it can be used in accordance with, forexample, the following formulations.

1. Capsules

    ______________________________________    (1) 2-ethoxy-1-  2'-(2,5-dihydro-5-oxo-1,2,4-                               10 mg    oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-    7-carboxylic acid    (2) lactose                90 mg    (3) microcrystalline cellulose                               70 mg    (4) magnesium stearate     10 mg    one capsule                180 mg    ______________________________________

(1), (2), (3) and a half of (4) are mixed and granulated. To thegranules is added the remainder of (4), and the whole is filled intogelatin capsules.

2. Tablets

    ______________________________________    (1) 2-ethoxy-1-  2'-(2,5-dihydro-5-oxo-1,2,4-                               10 mg    oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-    7-carboxylic acid    (2) lactose                35 mg    (3) corn starch            150 mg    (4) microcrystalline cellulose                               30 mg    (5) magnesium stearate     5 mg    one tablet                 230 mg    ______________________________________

(1), (2), (3), two thirds of (4) and a half of (5) are mixed andgranulated. To the granules are added the remainders of (4) and (5),followed by subjecting the mixture to compression molding.

3. Injections

    ______________________________________    (1) 2-ethoxy-1-  2'-(2,5-dihydro-5-oxo-1,2,4-                               10 mg    oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-    7-carboxylic acid disodium salt    (2) inositol               100 mg    (3) benzyl alcohol         20 mg    one ampoule                130 mg    ______________________________________

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is filled into an ampoule. The wholeprocess is conducted under sterile conditions.

4. Capsules

    ______________________________________    (1) 2-butyl-4-chloro-5-hydroxymethyl-1-  2'-(2,5,-                               10 mg    dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-    yl!methyl!imidazole    (2) lactose                90 mg    (3) microcrystalline cellulose                               70 mg    (4) magnesium stearate     10 mg    one capsule                180 mg    ______________________________________

(1), (2), (3) and a half of (4) are mixed and granulated. To thegranules is added the remainder of (4), and the whole is filled intogelatin capsules.

5. Tablets

    ______________________________________    (1) 2-butyl-4-chloro-5-hydroxymethyl-1-  2'-(2,5-                               10 mg    dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-    yl!methyl!imidazole    (2) lactose                35 mg    (3) corn starch            150 mg    (4) microcrystalline cellulose                               30 mg    (5) magnesium stearate     5 mg    one tablet                 230 mg    ______________________________________

(1), (2), (3), two thirds of (4) and a half of (5) are mixed andgranulated. To the granules are added the remainders of (4) and (5),followed by subjecting the mixture to compression molding.

6. Injections

    ______________________________________    (1) 2-butyl-4-chloro-5-hydroxymethyl-1-  2'-(2,5-                               10 mg    dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-    yl!methyl!imidazole sodium salt    (2) inositol               100 mg    (3) benzyl alcohol         20 mg    one ampoule                130 mg    ______________________________________

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is filled into an ampoule. The wholeprocess is conducted under sterile conditions.

7. Capsules

    ______________________________________    (1) 2-ethoxy-1-  2'-(2,5-dihydro-5-oxo-1,2,4-                               10 mg    thiadiazol-3-yl)biphenyl-4-yl!methyl!-    benzimidazole-7-carboxylic acid    (2) lactose                90 mg    (3) microcrystalline cellulose                               70 mg    (4) magnesium stearate     10 mg    one capsule                180 mg    ______________________________________

(1), (2), (3) and a half of (4) are mixed and granulated. To thegranules is added the remainder of (4), and the whole is filled intogelatin capsules.

8. Tablets

    ______________________________________    (1) 2-ethoxy-1-  2'-(2,5-dihydro-5-oxo-1,2,4-                               10 mg    thiadiazol-3-yl)biphenyl-4-yl!methyl!-    benzimidazole-7-carboxylic acid    (2) lactose                35 mg    (3) corn starch            150 mg    (4) microcrystalline cellulose                               30 mg    (5) magnesium stearate     5 mg    one tablet                 230 mg    ______________________________________

(1), (2), (3), two thirds of (4) and a half of (5) are mixed andgranulated. To the granules are added the remainders of (4) and (5),followed by subjecting the mixture to compression molding.

9. Injections

    ______________________________________    (1) 2-ethoxy-1-  2'-(2,5-dihydro-5-oxo-                               10 mg    1,2,4-thiadiazol-3-yl)biphenyl-4-    yl!methyl!benzimidazole-7-carboxylic    acid disodium salt    (2) inositol               100 mg    (3) benzyl alcohol         20 mg    one ampoule                130 mg    ______________________________________

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is filled into an ampoule. The wholeprocess is conducted under sterile conditions.

Working Example 1 2-Ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

1a) Methyl 3-amino-2- 2'-cyanobiphenyl-4-yl)methyl amino!benzoate

A mixture of methyl 22'-cyanobiphenyl-4-yl)methyl!amino!-3-nitrobenzoate (10 g) synthesizedin accordance with the method described in official gazette ofEP-0425921, FeCl₃.6H₂ O (0.1 g) and activated charcoal (1 g) in amixture of methanol (100 ml) and THF (50 ml) were heated under refluxfor 30 minutes. To the reaction mixture was added dropwise hydrazinehydrate (7.2 ml), followed by heating for 14 hours under reflux.Insoluble materials were filtered off, and the filtrate was concentratedto dryness. To the residue was added an aqueous solution of sodiumhydrogencarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with water and dried, then the solvent was evaporatedto dryness, followed by purifying the residue by column chromatographyon silica gel. Crystals thus obtained were recrystallized from isopropylether to afford pale yellow needles (6.0 g, 64%), m.p. 110°-111° C. ¹H-NMR(200 MHz,CDCl₃) δ: 3.81(3H,s), 3.97(2H,br s), 4.23(2H,d),6.39(1H,t), 6.84-6.93(2H,m), 7.26-7.55(8H,m), 7.64(1H,dt), 7.77(1H,dd).

1b) Methyl 1(2'-cyanobiphenyl-4-yl)methyl!-2-ethoxy-benzimidazole-7-carboxylate

To a solution of methyl 3-amino-2-(2'-cyanobiphenyl-4-yl)methyl!amino!benzoate (2.03 g) in ethylorthocarbonate (5 ml) was added acetic acid (0.37 g), and the mixturewas stirred for one hour at 80° C. The reaction mixture wasconcentrated, and the residue was dissolved in ethyl acetate. Thesolution was washed with an aqueous solution of sodium hydrogencarbonateand water. The solvent was evaporated to dryness to give crystals.Recrystallization of the crystals from ethyl acetate-hexane affordedcolorless crystals (2.01 g, 86%).

m.p.168.5°-169.5° C.

Elemental Analysis for C₂₅ H₂₁ N₃ O₃ :

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  72.98;         5.14;   10.21    Found:   72.71;         5.12;   9.97    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 3.71(3H,s),4.63(2H,q,J=7.1 Hz), 5.59(2H,s), 7.09(2H,d,J=8.4 Hz), 7.20(1H,t,J=7.9Hz), 7.45-7.59(5H,m), 7.69-7.80(2H,m), 7.92(1H,dd,J=1.4, 7.8 Hz).

IR(KBr)cm⁻¹ : 2225, 1725, 1550, 1480, 1430, 1350, 1280, 1250, 1040, 760,750.

1c) Methyl 2-ethoxy-1-2'-hydroxycarbamimidoyl)biphenyl)-4-yl!methyl!-1H-benzimidazole-7-carboxylate

To a mixture of hydroxylamine hydrochloride (6.95 g) in dimethylsulfoxide (DMSO) (80 ml) was added a solution of 28% NaOMe in methanol(5.2 g) while stirring at room temperature. The mixture was stirred for10 minutes at room temperature, to which was added the compound (8.22 g)obtained in Working Example (1b), and then the mixture was stirred for 4hours at 90° C. To the stirred reaction mixture was added water (50 ml)at room temperature. Resulting crystalline precipitates were collectedby filtration, washed with water and dried to give white powder (8.0 g,90%)

¹ H-NMR(90 MHz,CDCl₃) δ: 1.43(3H,t), 3.73(3H,s), 4.67(2H,q), 5.63(2H,s),6.97-7.80(11H,m). IR(Nujol)cm⁻¹ : 3420, 3320, 1720, 1545, 1430, 1280,1040, 750.

1d) Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

To a stirred suspension of the compound obtained in Working Example 1c)and triethylamine (0.2 g) in tetrahydrofuran (THF) (30 ml) was addeddropwise a methylene chloride (2 ml) solution of ethyl chlorocarbonate(0.22 g) under ice-cooling. The mixture was stirred for two hours atroom temperature, then insolubles were filtered off, and the filtratewas concentrated to dryness. To the concentrate was added ethyl acetate(5 ml), then insolubles were filtered off, and the filtrate wasconcentrated to dryness. The mixture of the residue in xylene (10 ml)was heated for 1.5 hour under reflux. To the reaction mixture was addedethyl acetate, which was washed with water, dried, and concentrated todryness. The residue was purified by column chromatography on silica gelto give crude crystals. Recrystallization from ethyl acetate-isopropylether afforded colorless prisms (0.22 g, 23%), m.p.195°-197° C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₅ :

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  66.38;         4.71;   11.91    Found:   66.17;         4.66;   11.84    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.43(3H,t), 3.77(3H,s), 4.60(2H,q), 5.63(2H,s),7.00-7.73(11H,m).

IR(Nujol)cm⁻¹ : 2740, 2670, 1775, 1720, 1545, 1450, 1435, 1275, 1040,750.

1e) 2-Ethoxy-1- 2'-2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

The compound obtained in Working Example 1d) (0.165 g) was dissolved inmethanol (12 ml), to which was added a 2N aqueous solution of LiOH (1ml), followed by heating for 3 hours under reflux. The reaction wasadjusted to pH 3 with 2N HCl, then the solvent was evaporated todryness. The residue was partitioned between water (20 ml) andchloroform (50 ml), then the organic layer was washed with water anddried. The solvent was evaporated to dryness, and the crystallineproduct was crystallized from ethyl acetate to give colorless prisms(0.135 g, 84%), m.p.156°14 157° C.

Elemental Analysis for C₂₅ H₂₀ N₄ O₅.1/2C₄ H₈ O₂ 1/5H₂ O:

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  64.33;         4.88;   11.11    Found:   64.37;         4.89;   11.04    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.47(3H,t), 4.60(2H,q), 5.67(2H,s),6.97-7.77(11H,m)

IR(Nujol)cm⁻¹ : 1775, 1730, 1685, 1540, 1425, 1270, 1030, 750.

Working Example 2 Methyl 2-butyl-1-2'-(2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl)biphenyl!methyl!benzimidazole-7-carboxylate

In DMSO (3 ml) were dissolved methyl 2-butyl-1-(2'-cyanobiphenyl-4-yl)methyl!benzimidazole-7-carboxylate (1.27 g)synthesized in accordance with the disclosure in a known literaturereference (official gazette of EP-0425921) and hydroxylaminehydrochloride (0.35 g). To the solution was added a solution of 28%sodium methoxide in methanol (0.965 g), and the mixture was stirred for3 hours at 90°-100° C. To the reaction mixture was added water (20 ml),and then resulting precipitates were filtered off. The filtrate wasconcentrated to dryness, and the residue was purified by means of asilica gel column chromatography to give a pale brown powdery product.The product (0.427 g) and pyridine (0.183 g) were dissolved in methylenechloride (3 ml). To the solution was added dropwise, while cooling at-20° to -25° C., thionyl chloride (1.19 g). The mixture was stirred fora while, to which was added water (3 ml) dropwise at -5° to -10° C. Tothe reaction mixture was added water (15 ml), and the mixture wasextracted with methylene chloride (20 ml). The organic layer was washedwith water, dried and concentrated to dryness. The residue was purifiedby column chromatography on silica gel. Crude crystals thus obtainedwere recrystallized from isopropyl ether to afford colorless prisms(0.12 g, 7%), m.p.124°-125° C.

Elemental Analysis for C₂₇ H₂₆ N₄ O₄ S.1/5C₆ H₁₄ O.1/5H₂ O:

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  64.02;         5.56;   10.59    Found:   64.11;         5.52;   10.51    ______________________________________

¹ H-NMR(90 MHz, CDCl₃) δ: 0.90(3H,t), 1.20-2.00(4H,m), 2.63(2H,t),3.70(3H,s), 5.63(2H,s), 6.73(2H,d), 7.00-7.70 (8H,m), 7.83-7.93(1H,m)

IR(Nujol)cm⁻¹ : 1725, 1520, 1435, 1410, 1290, 1180.

MS m/z:502(M⁺), 438, 423, 381, 192, 64

Working Example 3 Methyl 2-ethoxy-1-2'-(2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl)biphenyl!methyl!benzimidazole-7-carboxylate

To a solution of the compound (2.0 g) obtained in Working Example (1c)in THF (100 ml) was added pyridine (0.711 g). The mixture was addeddropwise over a period of 45 minutes, under ice-cooling, to a methylenechloride (20 ml) solution containing thionyl chloride (0.536 g). To themixture was added water (15 ml) dropwise under ice-cooling. The solventwas evaporated to dryness. To the residue was added water (50 ml), andthe mixture was extracted with chloroform (100 ml). The extract wasconcentrated to dryness, and the residue was purified by columnchromatography. Resultant crystals were recrystallized from ethylacetate to give colorless prisms (0.35 g, 16%), m.p.109°-111° C.

Elemental Analysis for C₂₅ H₂₂ N₄ O₅ S.1/5H₂ O:

    ______________________________________            C(%)  H(%)         N(%)    S(%)    ______________________________________    Calcd.:   60.77;  4.53;        11.34;                                         6.49    Found:    60.76;  4.49;        11.11;                                         6.48    ______________________________________

¹ H-NMR (90 MHz, CDCl₃) δ: 1.47(3H,t), 3.73(2H,s), 4.53(2H,q),5.60(2H,s), 6.90-7.93(11H,m).

IR(Nujol)cm⁻¹ : 1720, 1545, 1430, 1280, 1040, 750.

Working Example 4 1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The compound (0.51 g) obtained in Working Example (1e) was dissolved indimethylformamide (8 ml). To the solution were added1-(cyclohexyloxycarbonyloxy)ethyl chloride (0.3 g), anhydrous potassiumcarbonate (0.4 g) and potassium iodide (0.04 g). The mixture was stirredfor 15 hours at 80° C. The solvent was evaporated to dryness. To theresidue were added chloroform (100 ml), water (5 ml) and ethanol (5 ml),and the mixture was shaken. The lower layer was concentrated to drynessunder reduced pressure, and the residue was purified by columnchromatography on silica gel. Recrystallization from isopropyl etherafforded the title compound as colorless prisms (0.2 g, 36%),m.p.108°-109° C.

Elemental Analysis for C₃₄ H₃₄ N₄ O₈.0.5H₂ O:

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  64.24;         5.55;   8.81    Found:   64.43;         5.50;   8.79    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.07-2.00(16H,m), 4.03-4.67(3H,m), 5.63(2H,s),6.57-7.90(12H,m), 10.57(1H,broad).

IR(Nujol)cm⁻¹ : 1780, 1750, 1545, 1275, 1235, 1070, 1030.

Working Example 5 2-Ethylthio-4-methyl-1-2'-(2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!-1H-thieno3,4-d!imidazole-6-carboxylic acid

5a) O-methyl (4'-methylbiphenyl-2-yl) carbonylthio-carbamate

In chloroform (40 ml) was dissolved (4'-methylbiphenyl-2-yl)carboxylicacid (10 g). To the solution was added thionyl chloride (7 ml), and themixture was heated for 3 hours under reflux. The reaction mixture waspoured into ice-water, then the organic layer was separated, washed withwater and concentrated to dryness to give a syrup, which was dissolvedin dioxane (80 ml). To the solution was added powdered potassiumthiocyanate (9.16 g), and the mixture was heated for one hour underreflux. The reaction mixture was allowed to cool, and then insolubleswere filtered off. After addition of methanol (15 ml) to the filtrate,the solution was heated for 15 minutes under reflux. The reactionsolution was concentrated to dryness, and the resulting crystals werecrystallized from isopropyl ether to afford the title compound as whiteplates (7.4 g, 55%), m.p.149°-150° C.

¹ H-NMR(200 MHz,CDCl₃):2.40(3H,s), 4.01(3H,s), 7.23-7.34(4H,m),7.38-7.60(3H,m), 7.74(1H,dd), 8.37(1H,br s).

5b) Dimethyl (4'-methylbiphenyl-2-yl) carbonylimino monothiocarbonate

To a solution of the compound (7.4 g) obtained in Working Example (5a)in methanol (35 ml) were added methyl iodide (4.0 g) and a solution of28% sodium methoxide in methanol (5.5 g), and then the mixture wasstirred for 24 hours at room temperature. The reaction mixture wasconcentrated to dryness, and the residue was extracted with ethylacetate-water. The organic layer was washed with water and concentratedto dryness. The residue was purified by column chromatography on silicagel to give a colorless syrup (4.4 g, 57%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.29(3H,s), 3.36(3H,s), 2.37(3H,s),7.13-7.27(4H,m), 7.32-7.53(3H,m), 7.93(1H,m).

5c) 3-Methoxy-5-(4'-methylbiphenyl-2-yl)-1,2,4-oxadiazole

To a solution of potassium hydroxide (1.1 g) in methanol (20 ml) wasadded powdered hydroxylamine hydrochloride (1.2 g), and the mixture wasshaken well. The mixture was added to a solution of the compound (4.4 g)obtained in Working Example (5b) in 95% ethanol (10 ml), and theresultant mixture was stirred for 18 hours at room temperature. Thereaction mixture was concentrated to dryness, and to the residue wasadded chloroform. Insoluble materials were filtered off, and thefiltrate was concentrated to dryness, and the residue was dissolved intoluene (50 ml). The solution was heated for 2 hours under refluxtogether with a catalytic amount of p-toluenesulfonic acid, followed byconcentration to dryness. The residue was purified by columnchromatography on silica gel to afford a colorless syrup (2.5 g, 64%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.38(3H,s), 4.08(3H,s), 7.11-7.21(4H,m),7.41-7.62(3H,m), 7.96(1H,dd).

5d) 5-(4'-methylbiphenyl-2-yl)-1,2,4-oxadiazolin-3(2H)-one

A mixture of the compound (0.5 g) obtained in Working Example (5c) andpyridinium chloride (5 g) was heated for 30 minutes at 155° C. innitrogen atmosphere. The reaction mixture was extracted with ethylacetate-water. The organic layer was washed with water and concentratedto dryness to give pale yellow prisms (0.5 g, 100%), m.p.145°-150° C.

¹ H-NMR(200 MHz, CDCl₃) δ: 2.36(3H,s), 7.09-7.20(4H,m), 7.44-7.53(2H,m),7.58-7.67(1H,m), 7.88(1H,dd).

IR(Nujol)cm⁻¹ : 1605, 1590, 1480, 1340, 815, 750.

5e) 5-(4'-Methylbiphenyl-2-yl)-2-trityl-1,2,4- oxadiazol-3(2H)-one

To a solution of the compound (1 g) obtained in Working Example (5d) andtrityl chloride (1.0 g) in dichloromethane (20 ml) was added dropwisewith stirring. The mixture was then stirred for one hour at roomtemperature. The reaction mixture was concentrated to dryness, and theresidue was purified by column chromatography on silica gel to affordcolorless prisms (0.9 g, 45%), m.p.181°-184° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.37(3H,s), 7.06(4H,s), 7.16-7.43(17H,m),7.52-7.60(1H,m), 7.79(1H,dd).

IR(Nujol)cm⁻¹ : 1745, 1595, 1580, 1440, 1335, 1160.

5f) 5-(4-Bromomethylbiphenyl-2-yl)-2-trityl-1,2,4-oxadiazol-3(2H)-one

A mixture of the compound (0.9 g) obtained in Working Example (5e),N-bromosuccinimide (0.3 g) and a catalytic amount of benzoyl peroxidewas heated under reflux for one hour in carbon tetrachloride (20 ml)under irradiation of light. The reaction mixture was allowed to cool,and then precipitates were filtered off. The filtrate was concentratedto dryness to give the title compound as pale yellow amorphous powder(1.0 g, 99%).

¹ H-NMR(200 MHz,CDCl₃) δ: 4.47(2H,s), 7.06-7.63(22H,m), 7.85(1H,dd).

5g) Methyl 2-ethylthio-4-methyl-1-2'-(2,3-dihydro-3-oxo-2-trityl-1,2,4-oxadiazol-5-yl!biphenyl-4-yl!methyl!-1H-thieno3,4-d!imidazole-6-carboxylate

To a stirred solution of methyl2-ethylthio-4-methyl-1H-thieno(3,4-d!imidazole-6-carboxylate (0.4 g) indimethylformamide (10 ml) was added, in portions, sodium hydride (60%dispersion in meneral oil; 70 mg) under ice-cooling. The mixture wasstirred for further 30 minutes at room temperature. To the reactionmixture was added the compound (1 g) obtained in Working Example (5f),and the mixture was stirred for 1.5 hour. The reaction mixture wasconcentrated to dryness, and the residue was extracted with ethylacetate-water. The organic layer was washed with water, and thenconcentrated to dryness. The residue was purified by columnchromatography on silica gel to afford the title compound as yellowamorphous powder (0.6 g, 51%).

¹ H-NMR(200 MHz, CDCl₃) δ: 1.32(3H,t), 2.66(3H,s), 3.61(3H,s),3.25(2H,q), 5.75(2H,s),7.10(4H,s), 7.19(15H,s), 7.26-7.43(2H,m),7.52-7.60(1H,m), 7.70(1H,dd).

IR(Nujol)cm⁻¹ : 1740, 1685, 1595, 1330, 1315, 1160, 1080

5h) Methyl 2-ethylthio-1-2'-(2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl)-biphenyl-4-yl!methyl!-4-methyl-1H-thieno3,4!-d!imidazole-6-carboxylate

The compound (0.6 g) obtained in Working Example (5g) was dissolved inmethanol (15 ml) and chloroform (10 ml). To the solution was added1N-HCl (0.9 ml), and the mixture was stirred for one hour at roomtemperature. The reaction mixture was concentrated to dryness, and theresidue was partitioned between chloroform-water. The organic layer waswashed with water and concentrated to dryness. The resulting residue waspurified by column chromatography on silica gel to afford the titlecompound as pale yellow amorphous powder (0.4 g, 95%).

Elemental Analysis for C₂₅ H₂₂ N₄ O₄ S₂.2/5CH₂ Cl₂ :

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  56.44;         4.25;   10.36    Found:   56.56;         4.18;   10.26    ______________________________________

¹ H-NMR(200 Hz,d₆ -DMSO) δ: 1.35(3H,t), 2.56(3H,s), 3.70(3H,s),3.26(2H,s), 5.67(2H,s), 7.12(2H,d), 7.21(2H,d), 7.41-7.68(3H,m),7.80(1H,d).

IR(Nujol)cm⁻¹ : 1685, 1590, 1530, 1355, 1315, 1230, 1160, 1085.

5i) 2-Ethylthio-1-2'-(2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!-4-methyl-1H-thieno3,4-d!imidazole-6-carboxylic acid

The compound (0.1 g) obtained in Working Example (5h) was dissolved intetrahydrofuran (2 ml) and water (1 ml). To the solution was addedlithium hydroxide monohydrate (25 mg), and the mixture was heated for 17hours under reflux. The reaction mixture was concentrated to dryness, towhich was added water, and then insoluble materials were filtered off.The filtrate was made acid with 1N-HCl, and then resulting precipitateswere collected by filtration to obtain the title compound as pale yellowpowder (60 mg, 62%), m.p.144°-147° C.

Elemental Analysis for C₂₄ H₂₀ N₄ O₄ S₂ :

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  58.52;         4.09;   11.37    Found:   58.47;         4.25;   11.33    ______________________________________

¹ H-NMR(200 MHz,d₆ -DMSO) δ: 1.34(3H,t), 2.54(3H,s), 3.25(2H,q),5.70(2H,s), 7.16(2H,d), 7.20(2H,d), 7.45-7.73(3H,m), 7.88(1H,d).

IR(Nujol)cm⁻¹ : 1650, 1590, 1525, 1310, 1160, 1085.

Working Example 6 2-Butyl-1-2-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5yl)-biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

6a) 4'-methylbiphenyl-2-carbohydrazide

To a solution of 4'-methylbiphenyl-2-carboxylic acid (6.4 g) intetrahydrofuran (50 ml) were added N,N-dimethylformamide (two drops) andoxalyl chloride (4.4 g). The mixture was stirred for 16 hours at roomtemperature. The solvent was evaporated to dryness under reducedpressure to give an oil, which was added dropwise to a solution ofhydrazine monohydrate (7.5 g) in tetrahydrofuran (50 ml) with stirring,followed by stirring for further 6 hours. The reaction mixture wasdiluted with water, which was extracted with ethyl acetate. The extractwas washed with water and dried. The solvent was evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography on silica gel to give crude crystals. Recrystallizationfrom chloroform-isopropyl ether afforded the title compound as colorlessneedles (4.3 g, 63%), m.p.98°-99° C.

Elemental Analysis for C₁₄ H₁₄ N₂ O:

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  74.31;         6.24;   12.38    Found:   74.17;         6.17;   12.46    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.39(3H,s), 2.65(2H,br), 6.52(1H,br),7.20-7.31(4H,m), 7.35-7.55(3H,m), 7.67(1H,dd).

IR(KBr)cm⁻¹ : 3280, 3220, 1670, 1610, 1520, 1320, 1185, 1100, 820, 755.

6b) 1- 2-(4'-Methylphenyl)benzoyl!semicarbazide

To a solution of the compound (4.3 g) obtained in Working Example (6a)in 1N-HCl (20 ml) was added dropwise an aqueous solution (20 ml) ofsodium isocyanate (1.7 g), and the mixture was stirred for 3.5 hours.Resulting crystalline precipitates were collected by filtration andrecrystallized from ethyl acetate-methanol to give colorless needles(4.5 g, 87%), m.p.183°-184° C. (decomp.).

Elemental Analysis for C₁₅ H₁₅ N₃ O₂.0.3H₂ O:

    ______________________________________           C(%)         H(%)    N(%)    ______________________________________    Calcd.:  65.59;         5.72;   15.30    Found:   65.79;         5.61;   15.38    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.33(3H,s), 5.71(2H,br), 7.18(2H,d),7.33-7.56(6H,m), 7.84(1H,s), 9.84(1H,br).

IR(KBr)cm⁻¹ : 3460, 3230, 1700, 1650, 1520, 1305, 820, 765.

6c) 2,3-Dihydro-5-(4'-methylbiphenyl-2-yl)-1,3,4-oxadiazol-2(3H)-one

The compound (4.0 g) obtained in Working Example (6b) was suspended inxylene (100 ml), and the mixture was heated for 18 hours under reflux.The solvent was evaporated to dryness under reduced pressure, and theresidue was purified by column chromatography on silica gel to givecrude crystals. Recrystallization from ethyl acetate-hexane afforded thetitle compound as colorless needles: (2.0 g, 53%), m.p.130°-131° C.

Elemental Analysis for C₁₅ H₁₂ N₂ O₂ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   71.42;        4.79;  11.10    Found:    71.45;        4.79;  11.05    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.39(3H,s), 7.19(4H,s), 7.37-7.60(3H,s),7.77(1H,dd), 8.89(1H,br).

IR(KBr)cm⁻¹ : 1765, 1600, 1490, 1330, 1240, 1035, 960, 925, 815, 770,750, 715, 700.

6d)2,3-dihydro-5-(4'-methylbiphenyl-2-yl)-3-triphenylmethyl-1,3,4-oxadiazol-2(3H)-one

To a solution of the compound (2.0 g) obtained in Working Example (6c)in methylene chloride (25 ml) were added triethylamine (0.89 g) andtriphenylmethyl chloride (2.5 g), and the mixture was stirred for onehour. The reaction mixture was washed with water, then dried. Thesolvent was evaporated to dryness under reduced pressure, and theresidue was purified by column chromatography on silica gel to affordthe title compound as colorless amorphous powder (4.0 g, 100%),m.p.60°-63° C.

Elemental Analysis for C₃₄ H₂₆ N₂ O₂ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   82.57;        5.30;  5.66    Found:    82.67;        5.37;  5.20    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.31(3H,s), 7.00(2H,d), 7.05-7.54(20H,m),7.68(1H,dd).

IR(KBr)cm⁻¹ : 1780, 1490, 1445, 1335, 1280, 1005, 875, 820, 770, 755,740, 700.

6e)5-(4'-Bromomethylbiphenyl-2-yl)-2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazole-2(3H)-one

To a solution of the compound (4.0 g) obtained in Working Example (6d)in carbon tetrachloride (50 ml) were added N-bromosuccinimide (1.4 g)and benzoyl peroxide (19 mg), and the reaction mixture was heated forone hour under reflux under irradiation of light. Insoluble materialswere filtered off, and the filtrate was concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel to afford the title compound as colorless amorphous powder(4.3 g, 93%).

¹ H-NMR(200 MHz,CDCl₃) δ: 4.42(2H,s), 7.10-7.56(22H,m), 7.72(1H,dd).

IR(KBr)cm⁻¹ : 1780, 1490, 1440, 1335, 1260, 1215, 1000, 870, 765, 740,700.

6f) Methyl-2- N-2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl!methyl-N-valeryl!amino-3-nitrobenzoate

To a solution of the compound (0.86 g) obtained in Working Example (6e)in acetonitrile (10 ml) were added methyl 3-nitro-2-valerylaminobenzoate(0.42 g) and potassium carbonate (0.26 g), and the mixture was heatedfor 36 hours under reflux. The reaction mixture was diluted in water,which was extracted with ethyl acetate. The extract was washed withwater and dried. The solvent was evaporated to dryness under reducedpressure, and the residue was purified by column chromatography onsilica gel. The oily product thus obtained was dissolved intrifluoroacetic acid (5 ml), and the solution was stirred for 30 minutesat 60° C. Trifluoroacetic acid was evaporated to dryness under reducedpressure. The residue was dissolved in ethyl acetate, which was washedwith an aqueous solution of sodium hydrogencarbonate and dried. Thesolvent was evaporated to dryness under reduced pressure, and theresidue was purified by column chromatography on silica gel to affordthe title compound as a yellow oily product (0.50 g, 63%).

¹ H-NMR(200 MHz,CDCl₃) δ: 0.85(3H,t), 1.18-1.36(2H,m), 1.58-1.71(2H,m),2.05-2.15(2H,m), 3.69(3H,s), 4.58(1H,d), 4.95(1H,d), 7.06-7.16(4H,m),7.34(1H,dd), 7.41-7.54(2H,m), 7.62(1H,t), 7.77(1H,dd), 8.02(1H,dd),8.17(1H,dd), 8.97(1H,br).

IR(neat)cm⁻¹ : 1815, 1780, 1730, 1660, 1530, 1445, 1390, 1370, 1340,1285, 1260, 1230, 750.

6g) Methyl 2-butyl-1-2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

To a solution of the compound (0.50 g) obtained in Working Example 6f)in methanol (10 ml) were added conc. HCl (1 ml) and iron powder (0.34g). The mixture was heated for 24 hours under reflux. Insolublematerials were filtered off, and the filtrate was concentrated todryness. The residue was diluted with water and extracted with ethylacetate. The extract was washed with water and dried. The solvent wasevaporated to dryness under reduced pressure, and the residue waspurified by column chromatography on silica gel. Crude crystals thusobtained were recrystallized from ethyl acetate-chloroform to afford thetitle compound as colorless crystals (73 mg, 16%), m.p.204-205° C.

Elemental Analysis for C₂₈ H₂₆ N₄ O₄ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   69.70;        5.43;  11.61    Found:    69.43;        5.49;  11.59    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.94(3H,t), 1.36-1.55(2H,m), 1.79-1.94(2H,m),2.94(2H,t), 3.73(3H,s), 5.78(2H,s), 6.84(2H,d), 7.16(2H,d),7.21-7.36(2H,m), 7.41-7.57(2H,m), 7.64(1H,dd), 7.77(1H,dd), 7.96(1H,dd),9.35(1H,br).

IR(KBr)cm⁻¹ : 1760, 1710, 1600, 1430, 1405, 1335, 1270, 750.

6h) 2-Butyl-1-2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

To a solution of the compound (30 mg) obtained in Working Example (6 g)in methanol (1 ml) was added 1N-NaOH (0.5 ml), and the mixture washeated for 1.5 hour under reflux. After evaporation of the solvent, theresidue was diluted with water, which was then adjusted to pH 3-4 with1N-HCl to precipitate crystals. The crystals were collected byfiltration and recrystallized from ethyl acetate-methanol to afford thetitle compound as colorless needles (16 mg, 54%), m.p.247°-248° C.

Elemental Analysis for C₂₇ H₂₄ N₄ O₄.0.5H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   67.91;        5.28;  11.73    Found:    68.19;        5.21;  11.89    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.98(3H,t), 1.40-1.60(2H,m), 1.81-1.97(2H,m),3.05(2H,t), 5.87(2H,s), 6.86(2H,d), 7.17(2H,d), 7.28(1H,t),7.36-7.62(3H,m), 7.67(1H,dd), 7.83(1H,dd), 7.99(1H,dd).

IR(KBr)cm⁻¹ : 1770, 1700, 1600, 1410, 1230, 740.

Working Example 7 2-Ethylthio-1-2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

7a) Methyl 2-ethylthio-1-2'-2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylate (0.26 g) in N,N-dimethyl formamide (2 ml)was added sodium hydride (60% dispersion in meneral oil; 44 mg), and themixture was stirred for 15 minutes, to which was then added5-(4'-bromomethylbiphenyl-2-yl)-2,3-dimethyl-3-triphenylmethyl-1,3,4-oxadiazol-2-one(0.57 g). The reaction mixture was stirred for 2 hours at roomtemperature, which was diluted with water and extracted with ethylacetate. The extract was washed with water and dried. The solvent wasevaporated to dryness under reduced pressure, and the residue wasdissolved in trifluoroacetic acid (5 ml). The solution was stirred for30 minutes at 60° C. and concentrated to dryness under reduced pressure,and the residue was dissolved in ethyl acetate. The solution was washedwith an aqueous solution of sodium hydrogencarbonate and dried. Thesolvent was evaporated to dryness under reduced pressure, and theresidue was purified by column chromatography on silica gel to givecrude crystals. Recrystallization from ethyl acetate afforded the titlecompound as yellow prisms (0.17 g, 33%), m.p.220°-221° C.

Elemental Analysis for C₂₅ H₂₂ N₄ O₄ S₂ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   59.27;        4.38;  11.06    Found:    59.18;        4.50;  10.91    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.62(3H,s), 3.30(2H,q),3.75(3H,s), 5.70(2H,s), 7.13-7.23(4H,m), 7.34-7.58(3H,m), 7.77(1H,dd),8.83(1H,br).

IR(neat)cm⁻¹ : 1770, 1695, 1600, 1530, 1445, 1340, 1320, 1240, 1195,1165, 1085, 1000, 750.

7b) 2-Ethylthio-1-2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

To a solution of the compound (0.12 g) obtained in Working Example (7a)in tetrahydrofuran (6 ml) was added a solution of lithium hydroxidemonohydride (60 mg) in water (3 ml). The mixture was stirred for 60minutes at 50°-60° C. The solvent was evaporated to dryness underreduced pressure. The residue was diluted with water, and the solutionwas adjusted to pH 3-4 with 1N-HCl to precipitate crystals. The crystalswere collected by filtration and recrystallized from ethylacetate-methanol to afford the title compound as yellow prisms (72 mg,60%), m.p.195°-196° C. (decomp.).

Elemental Analysis for C₂₄ H₂₀ N₄ O₄ S₂.0.2H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   58.10;        4.14;  11.29    Found:    58.13;        4.22;  11.22    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.34(3H,t), 2.55(3H,s), 3.25(2H,q),5.72(2H,s), 7.19(2H,d), 7.28(2H,d), 7.42(1H,dd), 7.49-7.67(2H,m),7.76(1H,dd), 12.40(1H,br).

IR(KBr)cm⁻¹ : 1760, 1685, 1600, 1440, 1330, 1185, 1160, 1080, 960, 925,760, 750.

Working Example 8 2-Ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

8a) Methyl 2-ethylthio-4-methyl-1-2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methylthieno3,4-d!imidazole-6-carboxylate

To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylate (3 g) in DMF (20 ml) was added sodiumhydride (60%, oil) (0.56 g), and the mixture was stirred for 10 minutes.To the ice-cooling mixture was added2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl bromide(6.1 g), and the mixture was stirred for two hours at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous saline solution. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel to afford the title compound as a pale yellow syrupy product(4.15 g, 58%).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.62(3H,s), 3.29(2H,q),3.77(3H,s), 5.71(2H,s), 7.16(4H,s), 7.42-7.62(3H,m), 7.83-7.88(1H,m).

IR(neat)cm⁻¹ : 1690, 1600, 1450, 1430, 1345; 1330, 1315, 1230, 1190,1160, 1090, 840, 820, 800, 755, 730.

8b) Methyl 2-ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

To a solution of the compound (4.15 g) obtained in Working Example (8a)in MeOH (50 ml)-CHCl₃ (10 ml) was added 1N-NaOH (10 ml), and the mixturewas stirred for 30 minutes at room temperature. The reaction mixture wasadjusted to pH 4 with 1N-HCl, to which was added water, followed byextraction with CHCl₃. The extract was washed with water, dried, andthen the solvent was evaporated to dryness under reduced pressure togive crude crystals. Recrystallization from ethylacetate-methanol-hexane afforded the title compound as colorless prisms(3.15 g, 91%), m.p.240°-241° C. (decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ O₄ S₂ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   59.27;        4.38;  11.06    Found:    59.07;        4.26;  11.00    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.61(3H,s), 3.29(2H,q),3.75(3H,s), 5.74(2H,s), 7.26(4H,s), 7.42(1H,dt), 7.51(1H,dd),7.61(1H,dt), 7.85(1H,dd), 7.90(1H, br s).

IR(KBr)cm⁻¹ : 1760, 1680, 1595, 1455, 1450, 1430, 1315, 1230, 1160,1085, 755.

8c) 2-Ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

To a solution of the compound (0.5 g) obtained in Working Example (8b)in tetrahydrofuran (THF) (5 ml)-H₂ O (2.5 ml) was added sodium hydroxidemonohydrate (0.12 g), and the mixture was heated for 7 hours underreflux. To the reaction mixture was added water, and the mixture wasadjusted to pH 3 with 1N-HCl. Resultant crystals were collected byfiltration and recrystallized from chloroform-methanol to give thetitled compound as colorless needles (0.36 g, 73%), m.p.217°-219° C.(decomp.).

Elemental Analysis for C₂₄ H₂₀ N₄ O₄ S.0.3H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   57.89;        4.17;  11.25    Found:    57.89;        4.02;  11.08    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.34(3H,t), 2.55(3H,s), 3.24(3H,q),5.71(2H,s), 7.19(2H,d), 7.28(2H,d), 7.49-7.72(4H,m)

IR(KBr)cm⁻¹ : 1750, 1640, 1620, 1585, 1520, 1450, 1305, 1250, 1235,1155, 760, 750.

Working Example 9 2-Methoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

9a) Methyl 2-ethylsulfinyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

To a solution of the compound (3.15 g) obtained in Working Example (8b)in methylene chloride (100 ml) was added m-chloro perbenzoate (1.3 g),and the mixture was stirred for 20 minutes at room temperature. To thereaction mixture was added a saturated aqueous solution of sodiumhydrogencarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with water and dried. The solvent was evaporated todryness and the residue was purified by silica gel column chromatographyto give crude crystals. Recrystallization from ethylacetate-methanol-hexane afforded the title compound as colorless needles(2.60 g, 80%), m.p.206°-208° C. (decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ O₅ S₂ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   57.46;        4.24;  10.72    Found:    57.28;        4.27;  10.45    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.27(3H,t), 2.71(3H,s), 3.38(2H,q),3.82(3H,s), 5.98(1H,d), 6.40(1H,d), 7.26(4H,m), 7.41-7.64(3H,m),7.81(1H,dd), 8.75(1H,br s).

IR(KBr)cm⁻¹ : 1770, 1685, 1450, 1420, 1315, 1235, 1090, 1050, 1040,1020, 780, 750.

9b) Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxy-4-methylthieno3.4-d!imidazole-6-carboxylate

To a suspension of the compound (0.79 g) obtained in Working Example(9a) in methanol (20 ml) was added sodium methoxide (28%, methanolsolution) (0.88 g), and the mixture was stirred for 30 minutes at roomtemperature. To the reaction mixture was added water, and the mixturewas adjusted to pH 4 with 1N-HCl and extracted with ethyl acetate,followed by washing with a saturated aqueous saline solution and drying.The solvent was evaporated to dryness under reduced pressure to givecrude crystals. Recrystallization from ethyl acetate-hexane afforded thetitle compound as colorless needles (0.71 g, 98%), m.p.207°-209° C.(decomp.).

Elemental Analysis for C₂₄ H₂₀ N₄ O₅ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   60.49;        4.23;  11.76    Found:    60.23;        4.29;  11.49    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.37(3H,s), 3.73(3H,s), 3.99(3H,s),5.59(2H,s), 7.25(4H,s), 7.38(1H,dd), 7.50(1H,dt), 7.61(1H,dt),7.83(1H,dd), 8.79(1H,br s).

IR(KBr)cm⁻¹ : 1750, 1685, 1610, 1570, 1525, 1450, 1440, 1430, 1375,1330, 1230, 1055, 750.

9c) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid

To a mixture of the compound (0.6 g) obtained in Working Example (9b) ina mixture of THF (10 ml)-water (5 ml) was added lithium hydroxidemonohydrate (0.16 g). The mixture was heated for 8 hours under reflux.To the reaction mixture was added water, and the mixture was adjusted topH 4 with 1N-HCl and extracted with chloroform. The extract was washedwith water and dried. The solvent was evaporated to dryness underreduced pressure to give crude crystals. Recrystallization from ethylacetate-methanol afforded the title compound as colorless needles (0.35g, 54%), m.p.183°-186° C. (decomp.).

Elemental Analysis for C₂₃ H₁₈ N₄ O₅ S.0.5AcOEt:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   59.28;        4.38;  11.06    Found:    58.94;        4.15;  11.18    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.48(3H,s), 4.06(3H,s), 5.56(2H,s),7.21-7.31(4H,m), 7.49-7.72(4H,m).

IR(KBr)cm⁻¹ : 1800, 1660, 1650, 1570, 1450, 1380, 1370, 1330, 1240, 760,730.

Working Example 10 2-Ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

10a) Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

To a solution of sodium (0.1 g) in ethanol (20 ml) was added thecompound (0.7 g) obtained in Working Example (9a), and the mixture wasstirred for 30 minutes at room temperature. To the reaction mixture wasadded water, and the mixture was adjusted to pH 4 with 1N-HCl, followedby extraction with ethyl acetate. The extract was washed with water anddried. The solvent was evaporated to dryness under reduced pressure togive crystals, which were suspended in methanol. To the suspension wasadded sodium methoxide (28%, methanol solution) (0.65 g), and themixture was heated for 7 hours under reflux. After addition of water,the mixture was adjusted to pH 4 with 1N-HCl, followed by extractionwith ethyl acetate. The extract was washed with water and dried, and thesolvent was evaporated to dryness under reduced pressure to give crudecrystals. Recrystallization from ethyl acetate-methanol-hexane affordedthe title compound as pale yellow prisms (0.5 g, 76%), m.p.215°-217° C.(decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ O₅ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   61.21;        4.52;  11.42    Found:    61.02;        4.32;  11.28    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.45(3H,s), 3.75(3H,s),4.45(2H,q), 5.59(2H,s), 7.23-7.33(4H,m), 7.38(1H,dd), 7.49(1H,dt),7.60(1H,dt), 7.84(1H,dd), 8.27(1H,br s).

IR(KBr)cm⁻¹ : 1760, 1685, 1610, 1570, 1530, 1460, 1445, 1435, 1410,1380, 1330, 1230, 1100, 1060, 760.

10b) 2-Ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

To a suspension of the compound (0.4 g) obtained in Working Example(10a) in a mixture of THF (10 ml) and water (5 ml) was added lithiumhydroxide monohydrate (0.1 g), and the mixture was heated for 12 hoursunder reflux. To the reaction mixture was added water, and the mixturewas adjusted to pH 4 with 1N--HCl. Recrystallization of the resultingcrystals from ethyl acetate-methanol afforded the title compound ascolorless prisms (0.31 g, 79%), m.p.206°-208° C. (decomp.).

Elemental Analysis for C₂₄ H₂₀ N₄ O₅ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   60.49;        4.23;  11.76    Found:    60.27;        4.15;  11.70    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.32(3H,t), 2.46(3H,s), 4.47(2H,q),5.56(2H,s), 7.27(4H,s), 7.49-7.72(4H,m)

IR(KBr)cm⁻¹ : 1760, 1650, 1640, 1600, 1570, 1525, 1460, 1445, 1330,1240, 760.

Working Example 11 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl-4-methyl-2-n-propoxythieno3,4-d!imidazole-6-carboxylic acid

11a) Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl!biphenyl-4-yl!methyl-4-methyl-2-n-propoxythieno3,4-d!imidazole-6-carboxylate

To a solution of sodium (0.1 g) in n-propanol (20 ml) was added thecompound (0.7 g) obtained in Working Example (9a), and the mixture wasstirred for 30 minutes at room temperature. To the reaction mixture wasadded water, and the reaction mixture was adjusted to pH 4 with 1N-HCl,followed by extraction with ethyl acetate. The extract was washed withwater and dried. The solvent was evaporated to dryness under reducedpressure to give crystals. The crystals were suspended in methanol, andto the suspension was added sodium methoxide (28%, methanol solution)(0.65 g). The mixture was heated for 7 hours under reflux. To thereaction mixture was added water, and the mixture was adjusted to pH 4with 1N HCl, followed by extraction with ethyl acetate. The extract waswashed with water and dried. The solvent was evaporated to dryness underreduced pressure to give crude crystals. Recrystallization from ethylacetate-methanol-hexane afforded the title compound as pale yellowprisms (0.5 g, 74%), m.p.213°-215° C. (decomp.).

Elemental Analysis for C₂₆ H₂₄ N₄ O₅ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   61.89;        4.79;  11.10    Found:    61.73;        4.63;  10.93    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.98(3H,t), 1.71-1.91(2H,m), 2.47(3H,s),3.76(3H,s), 4.37(2H,t), 5.59(2H,s), 7.23-7.34(4H,m), 7.37(1H,dd),7.49(1H,dt), 7.60(1H,dt), 7.83(1H,dd), 8.22(1H,br s).

IR(KBr)cm⁻¹ : 1760, 1690, 1615, 1570, 1530, 1460, 1445, 1430, 1410,1360, 1330, 1230, 1100, 1060, 755.

11b) 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl-4-methyl-2-n-propoxythieno3,4-d!imidazole-6-carboxylic acid

To a suspension of the compound (0.4 g) obtained in Working Example(11a) in a mixture of THF (10 ml) and water (5 ml) was added lithiumhydroxide monohydrate (0.1 g), and the mixture was heated for 12 hoursunder reflux. To the reaction mixture was added water, and the mixturewas adjusted to pH 4 with 1N--HCl. Resulting crystals were collected byfiltration and recrystallized from chloroform-methanol-ether to affordthe title compound as colorless needles (0.28 g, 72%), m.p.208°-209° C.(decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ O₅ S.0.3H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   60.55;        4.59;  11.30    Found:    60.58;        4.43;  11.39    ______________________________________

1H-NMR(200 MHz,DMSO-d₆) δ: 0.89(3H,t), 1.65-1.82(2H,m), 2.48(3H,s),4.38(2H,t), 5.59(2H,s), 7.28(4H,s), 7.49-7.74(4H,m).

IR(KBr)cm⁻¹ : 1760, 1650, 1645, 1605, 1570, 1530, 1460, 1445, 1325,1240, 760.

Working Example 12 2-Ethylamino-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

12a) methyl 2-ethylamino-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

A mixture of the compound (0.60 g) obtained in Working Example (9a) anda 70% aqueous solution of ethylamine (10 ml) was heated at 80° C. in anautoclave for two hours. The reaction mixture was concentrated todryness and adjusted to pH 4 with 1N-HCl. The mixture was extracted withchloroform, and the extract was washed with water and dried. The solventwas evaporated to dryness under reduced pressure, and the residue waspurified by column chromatography on silica gel to give crude crystals.Recrystallization from ethyl acetate-methanol-hexane afforded the titlecompound as pale orange needles (0.28 g, 45%), m.p.219°-221° C.(decomp.).

Elemental Analysis for C₂₅ H₂₃ N₅ O₄ S.0.5AcOEt (533.60):

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   60.78;        5.10;  13.12    Found:    60.52;        5.15;  12.93    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.26(3H,t), 2.40(3H,s), 3.31(2H,q),3.67(3H,s), 5.61(2H,s), 7.16(2H,d), 7.23(2H,d), 7.38(1H,dt),7.47(1H,dd), 7.58(1H,dt),7.72(1H,dd).

IR(KBr)cm⁻¹ : 3325, 1740, 1690, 1610, 1590, 1540, 1460, 1435, 1335,1230, 1090, 765.

12b) 2-Ethylamino-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

To a suspension of the compound (0.2 g) obtained in Working Example(12a) in a mixture of THF (5 ml) and water (2.5 ml) was added lithiumhydroxide monohydrate (51 mg), and the mixture was heated for 24 hoursunder reflux. To the reaction mixture was added water, and the mixturewas adjusted to pH 4 with 1N-HCl. Crystals precipitated were collectedby filtration and recrystallized from chloroform-methanol to afford thetitle compound as pale yellow crystals (0.12 g, 67%), m.p.189°-192° C.(decomp.).

Elemental Analysis for C₂₄ H₂₁ N₅ O₄ S.1.0MeOH (507.56):

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   59.16;        4.96;  13.80    Found:    59.34;        4.76;  14.00    ______________________________________

1H-NMR(200 MHz,DMSO-d₆) δ: 1.13(3H,t), 2.34(3H,s), 3.28(2H,q),5.84(2H,s), 7.06(2H,s), 7.22(2H,d), 7.28(1H,dd), 7.34-7.43(2H,m),7.47(1H,dd).

IR(KBr)cm⁻¹ : 1770, 1700, 1680, 1670, 1650, 1635, 1560, 1540, 1510.

Working Example 13 Acetoxymethyl 1-2'-(4-acetoxymethyl-4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethoxybenzimidazole-7-carboxylate

To a solution of the compound (1.02 g) obtained in Working Example 1 inDMF (4 ml) was added triethylamine (413 mg). To the stirred mixture wasadded acetoxymethyl chloride (444 mg) at room temperature, followed bystirring for 20 hours under the same conditions. To the reaction mixturewere added dichloromethane (40 ml), water (25 ml) and 2N-HCl (3 ml), andthe mixture was shaken. The organic layer was separated and concentratedto dryness under reduced pressure. The residue was purified by columnchromatography on silica gel to give crude crystals. Recrystallizationfrom ether-isopropyl ether afforded the title compound as colorlessprisms (350 mg, 30%), m.p.132°-133° C.

Elemental Analysis for C₃₁ H₂₈ N₄ O₉ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   62.00;        4.70;  9.33    Found:    62.08;        4.60;  9.29    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.47(3H,t), 1.77(3H,s), 2.10(3H,s), 4.67(2H,q),4.87(2H,s), 5.70(2H,s), 5.87(2H,s), 7.00-7.83(11H,m).

IR(Nujol)cm⁻¹ : 1790, 1760, 1730, 1200, 1035, 980.

Working Example 14 Acetoxymethyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The same reaction as in Working Example 13 was conducted, and thereaction mixture was purified by silica gel column chromatography togive crude crystals. Recrystallization from ethyl acetate-isopropylether afforded the title compound as colorless prisms (250 mg, 29%),m.p.11°-112° C.

Elemental Analysis for C₂₈ H₂₄ N₄ O₇.1/30C₆ H₁₄ O.1/5H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   63.24;        4.68;  10.46    Found:    63.31;        4.64;  10.20    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.40(3H,t), 2.00(3H,s), 4.40(2H,q), 5.67(2H,s),5.70(2H,s), 6.87-7.90(11H,m).

IR(Nujol)cm⁻¹ : 1780, 1730, 1545.

Working Example 15 1- 2'-(4-Acetoxymethyl-4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethoxybenzimidazole-7-carboxylate

The same reaction as in Working Example 13 was conducted, and thereaction mixture was purified by column chromatography on silica gel togive crude crystals, followed by recrystallization from ethyl acetate toafford the title compound as colorless prisms (50 mg, 5%), m.p.177°-179°C.

Elemental Analysis for C₂₈ H₂₄ N₄ O₇.1/3H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   62.92;        4.65;  10.48    Found:    62.86;        4.44;  10.35    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.47(3H,t), 1.77(3H,s), 4.70(2H,q), 4.80(2H,s),5.70(2H,s), 6.97-7.83(11H,m)

IR(Nujol)cm⁻¹ : 1785, 1760, 1690, 1550, 1205, 1035.

Working Example 16 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylpyrazolo1,5-b! 2,4!triazole-7-carboxylic acid

16a) Ethyl 1-2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylpyrazolo1,5-b! 1,2,4!triazole-7-carboxylate

To an ice-cooling solution of ethyl 2-propyl-1H-pyrazolo 1,5-b!1,2,4!triazole-7-carboxylate (0.4 g) in N,N-dimethylformamide (7 ml) wasadded sodium hydride (60% oil; 72 mg) under nitrogen atmosphere, and themixture was stirred for 30 minutes at the same temperature. To thereaction mixture was added a solution of the compound (1.15 g) obtainedin Working Example (22c) in N,N-dimethylformamide (7 ml). The mixturewas stirred for one hour under ice-cooling, then for 3 hours at roomtemperature. The reaction mixture was concentrated to dryness underreduced pressure. To the residue was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand dried, and then the solvent was evaporated to dryness under reducedpressure. The residue was purified by column chromatography on silicagel to afford the title compound as white amorphous powder (0.92 g,89%).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.01(3H,t), 1.30(3H,t), 1.70-1.88(2H,m),2.67(2H,t), 4.27(2H,q), 5.72(2H,s), 7.14(2H,d), 7.24(2H,d),7.40-7.60(3H,m), 7.90-7.94(1H,m), 8.00(1H,s).

IR(KBr)cm⁻¹ : 2970, 1692, 1600, 1538, 1470.

16b) Ethyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylpyrazolo1,5-b! 1,2,4!-triazole-7-carboxylate

To an ice-cooling solution of the compound (0.92 g) obtained in WorkingExample (16a) in a mixture of dioxane (8 ml) and water (2 ml) was added1N-NaOH (1.7 ml), and the mixture was stirred for 15 minutes underice-cooling. To the reaction mixture were added 1N-HCl (2.5 ml) andwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and dried, then the solvent was evaporatedto dryness under reduced pressure. The residue was crystallized fromethyl acetate-ether to afford the title compound as colorless crystals(0.666 g, 88%), m.p.227°-228° C.

Elemental Analysis for C₂₅ H₂₄ N₆ O₄ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   63.55;        5.12;  17.79    Found:    63.53;        5.20;  17.67    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.91(3H,t), 1.16(3H,t), 1.54-1.73(2H,m),2.73(2H,t), 4.16(2H,q), 5.75(2H,s), 7.26(2H,d), 7.32(2H,d),7.48-7.73(4H,m), 7.96(1H,s).

IR(KBr)cm⁻¹ : 3100, 2980, 1795, 1702, 1602, 1540, 1468.

16c) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl!methyl!-2-propylpyrazolo1,5! 1,2,4!-triazole-7-carboxylic acid

To a mixture of the compound (0.2 g) obtained in Working Example (16b)in a mixture of methanol(5 ml), tetrahydrofuran (5 ml) and water (5 ml)was added 2N--NaOH (2.1 ml), and the mixture was heated for 3 hoursunder reflux. The reaction mixture was cooled, to which were added2N-HCl (3.0 ml) and water, followed by extraction with ethyl acetate.The organic layer was washed with water and dried, and the solvent wasevaporated to dryness under reduced pressure. The residue wasrecrystallized from ethyl acetate to afford the title compound ascolorless crystals (0.17 g, 90%), m.p.223°-225° C.

Elemental Analysis for C₂₃ H₂₀ N₆ O₄.0.2AcOEt:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   61.87;        4.71;  18.19    Found:    61.81;        4.66;  18.28    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.90(3H,t), 1.52-1.70(2H,m), 2.71(2H,t),5.79(2H,s), 7.32(4H,s), 7.50-7.73(4H,m), 7.92(1H,s), 12.35(1H,br s).

IR(KBr)cm⁻¹ : 3060, 2960, 2700-2200, 1783, 1668, 1590, 1540, 1483.

Working Example 17 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl-2-propylimidazo1,2-b!pyrazole-7-carboxylic acid

17a) Ethyl 2-propyl-1-2'-(5-trichloromethyl-1,2,4-oxadiazole-3-yl)biphenyl-4-yl!methyl!imidazo1,2-b!-pyrazole-7-carboxylate

By the similar reaction procedure as in Working Example (16a), the titlecompound was obtained as a pale yellow oil (0.16 g, 47%) from ethyl2-propyl-1H-imidazo 1,2-b!pyrazole-7-carboxylate (0.132 g).

¹ H-NMR(200 MHz,CDCl₃) δ: 0.98(3H,t), 1.28(3H,t), 1.53-1.72(2H,m),2.46(2H,t), 4.23(2H,q), 5.75(2H,s), 7.05(2H,d), 7.14(1H,s), 7.18(2H,d),7.41-7.63(3H,m), 7.86-7.91(1H,m), 8.01(1H,s).

IR(Neat)cm⁻¹ : 2975, 1702, 1690, 1603, 1582, 1562, 1495.

17b) Ethyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylimidazo1,2-b!pyrazole-7-carboxylate

By the similar reaction procedure as in Working Example (16b), the titlecompound was obtained as colorless crystals (84 mg, 68%), m.p.204°-206°C. (ethyl acetate-ether) from the compound obtained in Working Example(17a) (0.15 g).

Elemental Analysis for C₂₆ H₂₅ N₅ O₄.0.5H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   64.99;        5.45;  14.57    Found:    65.27;        5.50;  14.38    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.99(3H,t), 1.27(3H,t), 1.53-1.72(2H,m),2.48(2H,t), 4.18(2H,q), 5.74(2H,s), 7.13(2H,d), 7.13(1H,s), 7.27(2H,d),7.38-7.65(3H,m), 7.80-7.84(1H,m), 7.92(1H,s), 8.31(1H,br).

IR(KBr)cm⁻¹ : 3125, 2960, 1780, 1705, 1600, 1587, 1492, 1470.

17c) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl!methyl!-2-propylimidazo1,2-b!pyrazole-7-carboxylic acid

By the similar reaction procedure as in Working Example (16c), the titlecompound was obtained as colorless crystals (48 mg, 57%), m.p.191°-196°C. (decomp.) (methanol-water), from the compound obtained in WorkingExample (17b) (90 mg).

Elemental Analysis for C₂₄ H₂₁ N₅ O₄ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   65.00;        4.77;  15.79    Found:    65.28;        4.68;  15.72    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.89(3H,t), 1.43-1.62(2H,m),2.43-2.51(2H,m), 5.80(2H,s), 7.18(2H,d), 7.29(2H,d), 7.50-7.72(5H,m),11.87(1H,br s), 12.36(1H,br s).

IR(KBr)cm⁻¹ : 3025, 2960, 1700-2200, 1780, 1643, 1595, 1580, 1498.

Working Example 18 Ethyl 2-ethyl-4,7-dihydro-7-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-oxothieno2,3-b!pyridine-5-carboxylate

18a) Ethyl 7-2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethyl-4,7-dihydro-4-oxothieno2,3-b!pyridine-5-carboxylate

To an ice-cooling solution of ethyl 2-ethyl-4-hydroxythieno2,3-b!pyridine-5-carboxylate (0.252 g) in N,N-dimethylformamide (DMF) (7ml) was added, under nitrogen atmosphere, sodium hydride (60% in oil; 40mg), and the mixture was stirred for 30 minutes. To the reaction mixturewas added a solution of the compound obtained in Working Example (22c)(0.6 g) in N,N-dimethylformamide (4 ml), and the mixture was stirred for2 hours at room temperature. The reaction mixture was concentrated todryness under reduced pressure. To the residue was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and dried, and the solvent was evaporated to dryness underreduced pressure, The residue was purified by column chromatography onsilica gel to afford the tile compound as white powder (0.5 g, 83%).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.32(3H,t), 1.41(3H,t), 2.82(2H,d-q),4.40(2H,q), 5.22(2H,s), 7.23-7.33(5H,m), 7.43-7.65(3H,m),7.93-7.98(1H,m), 8.39(1H,s).

IR(KBr)cm⁻¹ : 2975, 1672, 1620, 1580, 1493.

18b) Ethyl 2-ethyl-4,7-dihydro-7-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-oxothieno2,3-b!pyridine-5-carboxylate

To an ice-cooling solution of the compound (0.49 g) obtained in WorkingExample (18a) in a mixture of dioxane (8 ml), tetrahydrofuran (THF) (8ml) and water (4 ml) was added 1N-NaOH (0.9 ml). After stirring for 40minutes under ice-cooling, to the mixture was added 1N-NaOH (0.4 ml),and the mixture was stirred for 20 minutes under ice-cooling. To thereaction mixture were added 1N-HCl (2,0 ml) and water, followed byextraction with ethyl acetate. The organic layer was washed with waterand dried, then the solvent was evaporated to dryness under reducedpressure. The residue was crystallized from methanol to afford thetitled compound as colorless crystals (0.278 g, 68%), m.p.243°-235° C.

Elemental Analysis for C₂₇ H₂₃ N₃ O₅ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   64.66;        4.62;  8.38    Found:    64.70;        4.70;  8.33    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.22(3H,t), 1.29(3H,t), 2.79(2H,d-q),4.23(2H,q), 5.50(2H,s), 7.10(1H,t), 7.31-7.40(4H,m), 7.50-7.73(4H,m),8.77(1H,s), 12.37(1H,br s)

IR(KBr)cm⁻¹ : 3430, 2980, 1782, 1727, 1602, 1542, 1500.

Working Example 19 3-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propyl-4(3H)-quinazolinone

19a) 3-2'-(5-Trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propyl-4(3H)-quinazolinone

To an ice-cooling solution of 2-propyl-4(3H)-quinazoline (0.283 g) inN,N-dimethylformamide (8 ml) was added sodium hydride (60% in oil; 60mg) under nitrogen atmosphere, and the mixture was stirred for 30minutes at the same temperature. To the reaction mixture was added asolution of the compound (0.78 g) obtained in Working Example (22c) inN,N-dimethylformamide (5 ml) and stirred for 4 hours at roomtemperature. The reaction mixture was concentrated to dryness underreduced pressure, and to the mixture was added water, followed byextraction with ethyl acetate. The organic layer was washed with waterand dried, and the solvent was evaporated to dryness under reducedpressure. The residue was purified by column chromatography on silicagel to afford the title compound as a colorless oil (0.5 g, 62%).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.02(3H,t), 1.75-1.94(2H,m), 2.75(2H,t),5.44(2H,s), 7.16(2H,d), 7.22(2H,d), 7.41-7.79(6H,m), 7.87-7.92(1H,m),8.28-8.32(1H,m).

IR(neat)cm⁻¹ : 2960, 1668, 1595, 1567.

19b) 3-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl!methyl!-2-propyl-4(3H)-quinazolinone

To a mixture of the compound (0.42 g) obtained in Working Example (19a)in a mixture of dioxane (6 ml) and water (1.5 ml) was added 1N-NaOH (1.0ml) under ice-cooling. The mixture was stirred for 30 minutes underice-cooling. To the reaction mixture were added 1N-HCl (2.0 ml) andwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and dried, and the solvent was evaporated todryness under reduced pressure. The residue was crystallized from ethylacetate-ether to afford the title compound as colorless crystals (0.311g, 91%), m.p.251°-253° C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₃ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   71.22;        5.06;  12.78    Found:    70.93;        5.04;  12.72    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.91(3H,t), 1.63-1.82(2H,m), 2.74(2H,t),5.45(2H,s), 7.24(2H,d), 7.31(2H,d), 7.49-7.74(6H,m), 7.80-7.88(1H,m),8.16-8.20(1H,m), 12.38(1H,br s).

IR(KBr)cm⁻¹ : 3120, 2970, 1768, 1638, 1605, 1590.

Working Example 20 Methyl 2-butyl-1-2'-(4,5-dihydro-5-oxo-6H-1,2,4-oxadiazin-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

20a) Methyl 2-butyl-1-2'-(O-ethoxycarbonylmethyl)hydroxycarbamimidoyl!biphenyl-4-yl!methyl!-benzimidazole-7-carboxylate

A mixture of the compound (2.20 g) obtained in Working Example (1c),ethyl bromoacetate (0.84 g) and potassium carbonate (0.67 g) inacetonitrile (20 ml) was stirred for 15 hours at room temperature. Tothe reaction mixture was added a saturated aqueous saline solution, andmixture was extracted with ethyl acetate. The extract was washed withwater and dried (MgSO₄), then the solvent was evaporated in vacuo. Theresidue was purified by silica gel (80 g) column chromatography to givethe title compound (1.10 g, 42%) as an oil.

¹ H-NMR(200 MHz,CDCl₃) δ: 0.96(3H,t,J=7.4 Hz), 1.28(3H,t,J=7.2 Hz),1.48(2H,m), 1.89(2H,m), 2.94(2H,t,J=7.6 Hz), 3.74(3H,s), 4.20(2H,q,J=7.2Hz), 4.45(2H,br s), 4.56(2H,s), 5.77(2H,s), 6.89(2H,d,J=8.0 Hz),7.19-7.70(8H,m), 7.94(1H,dd,J=1.2 Hz,7.8 Hz).

IR(Neat)cm⁻¹ : 3480, 3375, 3150, 1750, 1725, 1715, 1635, 1600.

20b) Methyl 2-butyl-1-2'-(4,5-dihydro-5-oxo-6H-1,2,4-oxadiazin-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

A mixture of the compound (1.10 g) obtained in Working Example (20a) andp-toluenesulfonic acid chloride (0.1 g) in toluene (20 ml) was heatedfor 18 hours under reflux. The reaction mixture was concentrated todryness, and the residue was extracted with chloroform. The extract waswashed with water and dried (MgSO₄), and the solvent was evaporated invacuo. The residue was purified by silica gel (80 g) columnchromatography to give the title compound as colorless crystals (0.25 g,25%), m.p.226°-227° C.

Elemental Analysis for C₂₉ H₂₈ N₄ O₄.1/2H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   68.90;        5.78;  11.08    Found:    69.06;        5.78;  10.73    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.90(3H,t,J=7.2 Hz), 1.40(2H,m), 1.77(2H,m),2.88(2H,t,J=7.4 Hz), 3.65(3H,s), 4.15(2H,s), 5.72(2H,s), 6.89(2H,d,J=8.4Hz), 7.27-7.64(8H,m), 7.87(1H,dd,J=1.0 Hz,8.0 Hz), 10.91(1H,br s).

IR(Nujol)cm⁻¹ : 1720, 1710, 1605.

Working Example 21 2-Butyl-1-2'-(2,4-dioxothiazolidin-5-yl)biphenyl-4-yl!methyl!benzimidazol

21a) 2-Butyl-1- 2'-hydroxymethylbiphenyl-4-yl!methyl!-benzimidazole

A stirred solution of 2-butyl-1-(2'-carboxy-biphenyl-4-yl)methyl!benzimidazole (1.50 g.) in benzene (30ml) was added dropwise to sodium dihydro-bis(2-methoxyethoxy)aluminate(70% toluene solution). The mixture was stirred for one hour at roomtemperature, and then heated for 10 minutes under reflux. The reactionmixture was cooled and poured into 2N-HCl, followed by extraction withdichloromethane. The extract was washed with water and dried (MgSO₄),and the solvent was evaporated in vacuo. The residue was purified bysilica gel (80 g) column chromatography to give the title compound (0.67g, 46%) as an oil, which was crystallized from ethyl acetate-ether toafford pale yellow prisms, m.p.162°-163° C.

Elemental Analysis for C₂₅ H₂₆ N₂ O.1/3H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   79.75;        7.14;  7.44    Found:    79.75;        7.01;  7.29    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.92(3H,t,J=7.2 Hz), 1.43(2H,m), 1.83(2H,m),1.86(1H,s), 2.87(2H,t,J=7.4 Hz), 4.57(2H,s), 5.39(2H,s), 7.09(2H,d,J=8.4Hz), 7.19-7.61(9H,m), 7.72-7.81(1H,m).

IR(Nujol)cm⁻¹ : 3170

21b) 2-Butyl-1- (2'-formylbiphenyl-4-yl)methyl!benzimidazole

A mixture of the alcohol (0.65 g) obtained in Working Example (21a) andpyridinium dichromate (0.67 g) in dichloromethane (20 ml) was stirredfor 15 hours at room temperature. Insoluble materials were filtered off,and the filtrate was concentrated to dryness. The residue was purifiedby silica gel (60 g) column chromatography to give the title compound asan oil (0.52 g, 80%), which was crystallized from isopropyl ether toafford colorless crystals (0.46 g, 71%),

m.p.117°-118° C.

Elemental Analysis for C₂₅ H₂₄ N₂ O.1/5H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   80.72;        6.61;  7.53    Found:    80.73;        6.55;  7.41    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.94(3H,t,J=7.2 Hz), 1.45(2H,m), 1.86(2H,m),2.88(2H,t,J=7.4 Hz), 5.42(2H,s), 7.14(2H,d,J=7.8 Hz), 7.21-7.68(8H,m),7.76-7.83(1H,m), 8.01(1H,dd,J=1.6 Hz,7.6 Hz), 9.94(1H,s).

IR(Nujol)cm⁻¹ : 1690, 1655, 1615, 1595.

21c) 2-Butyl-1-2'(2,4-dioxothiazolin-5-yl)biphenyl-4-yl!methyl!benzimidazole

To a stirred mixture of the aldehyde (0.44 g) obtained in WorkingExample (21b) in ethyl acetate (4 ml) and tetrahydrofuran (4 ml) wereadded an aqueous solution (2 ml) of sodium sulfite and an aqueoussolution (1.2 ml) of potassium cyanate (0.78 g). The reaction mixturewas stirred for 4 hours at room temperature and for further one hour at60° C. The reaction mixture was concentrated in vacuo, and to theresidue was added water, followed by extraction with chloroform. Theextract was washed with water and dried (MgSO₄), and the solvent wasevaporated in vacuo. The residue was crystallized from ether to givecyanohydrin (0.43 g, 91%) as colorless crystals. The product was usedfor the subsequent reaction without further purification.

¹ H-NMR(200 MHz,CDCl₃) δ: 0.78(3H,t,J=7.4 Hz), 1.25(2H,m), 1.61(2H,m),2.69(2H,t,J=7.6 Hz), 5.32(2H,s), 5.51(1H,s), 7.03(2H,d,J=8.0 Hz),7.11-7.60(9H,m), 7.92 (1H,dd,J=1.8 Hz, 7.6 Hz).

IR(Nujol;)cm⁻¹ : 3420, 2230, 1615.

To a solution of the cyanohydrin (0.41 g) obtained by theabove-mentioned reaction in chloroform (2.5 ml) was added thionylchloride (0.11 ml). The mixture was heated for 1.5 hour under refluxwith stirring. The reaction mixture was concentrated to dryness to givean oil. The mixture of the oil and thiourea (88 mg) in ethanol (10 ml)were heated for one hour under reflux. To the reaction mixture was added2N-HCl (10 ml), and the mixture was heated overnight (16 hours) underreflux. The reaction mixture was cooled and then diluted with water,followed by extraction with chloroform. The extract was washed withwater and dried (MgSO₄), and the solvent was evaporated in vacuo. Theresidue was purified by silica gel (70 g) column chromatography to givecrystals. Recrystallization from ethyl acetate afforded the titlecompound (0.31 g, 66%) as colorless prisms, m.p.249°-250° C.

Elemental Analysis for C₂₇ H₂₅ N₃ O₂ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   71.18;        5.53;  9.22    Found:    70.93;        5.51;  9.09    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.88(3H,t,J=7.4 Hz), 1.38(2H,m), 1.74(2H,m),2.87(2H,t,J=7.4 Hz), 5.52(1H,s), 5.56(2H,s), 7.13-7.64(12H,m),12.20(1H,br).

IR(Nujol)cm⁻¹ : 1690.

Working Example 22 2-Butyl-4-chloro-5-formyl-1-2'(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!imidazole

22a) 4'-Methylbiphenyl-2-carboxamidoxime

To a solution of hydroxylamine hydrochloride (17.9 g) in dimethylsulfoxide (120 ml) was added a methanol solution of sodium methoxideprepared from metallic sodium (5.92 g) and anhydrous methanol (50 ml).The mixture was stirred for 10 minutes at room temperature, to which wasadded 2'-cyano-4-methylbiphenyl (10 g). The reaction mixture was stirredfor 5 hours at 100° C. The reaction mixture was partitioned betweenethyl acetate and water. The aqueous layer was extracted with ethylacetate. Organic layers were combined, washed with water and dried, thenthe solvent was evaporated in vacuo. The residue was purified by columnchromatography on silica gel to afford the title compound as a whiteamorphous product (11.2 g, 96%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.39(3H,s), 4.42(2H,br s), 7.22(2H,d),7.31-7.50(5H,m), 7.56-7.60(1H,m).

IR(KBr)cm⁻¹ : 3490, 3380, 1642, 1575, 1568.

22b) 5-Trichloromethyl-3-(4'-methylbiphenyl-2-yl)-1,2,4-oxadiazole

To a solution of the compound (10 g) obtained by Working Example (22a)in benzene (100 ml) was added dropwise trichloroacetic anhydride (16.4g), and the reaction mixture was heated for two hours under reflux. Thereaction mixture was cooled and concentrated to dryness. The residue waspartitioned between ether and water. The aqueous layer was extractedwith ether. Organic layers were combined, washed with water and dried,and the solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel to afford the titlecompound as a pale yellow oil (12 g, 77%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.38(3H,s), 7.16(4H,s), 7.44-7.64(3H,m),7.88-7.93(1H,m).

IR(neat)cm⁻¹ : 3025, 1600, 1580, 1561, 1508.

22c) 3-(4'-Bromomethylbiphenyl-2-yl)-5-trichloromethyl-1,2,4-oxadiazole

To a solution of the compound (24.8 g) obtained in Working Example (22b)in carbon tetrachloride (300 ml) were added N-bromosuccinimide (12.5 g)and α,α'-azobisisobutyronitrile (1.15 g), and the mixture was heated fortwo hours under reflux. The reaction mixture was cooled, and whiteinsoluble materials were filtered off. The filtrate was diluted withdichloromethane. The organic layer was washed with water and dried, andthe solvent was evaporated in vacuo under reduced pressure. The residuewas recrystallized from ether-hexane to afford the title compound ascolorless crystals (23.0 g, 76%), m.p.77°-79° C.

Elemental Analysis for C₁₆ H₁₀ N₂ OBrCl₃.0.5H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   43.52;        2.51;  6.34    Found:    43.76;        2.33;  6.31    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 4.52(2H,s), 7.23(2H,d), 7.38(2H,d),7.44-7.65(3H,m), 7.91-7.95(1H,m).

IR(KBr)cm⁻¹ : 1600, 1560, 1475, 1428, 1332.

22d) 2-Butyl-4-chloro-1-2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5-formylimidazole

To a cooled solution of metallic sodium (25 mg) in anhydrous methanol (2ml) was added dropwise a solution of 2-butyl-4-chloro-5-formylimidazole(0.2 g) in methanol (3 ml) under nitrogen atmosphere. The mixture wasstirred for one hour at room temperature and concentrated to dryness. Toa solution of the residue in N,N-dimethylformamide (2 ml) was addeddropwise a solution of the compound (0.56 g) obtained in Working Example(22c) in N,N-dimethylformamide (3 ml) under ice-cooling. The reactionmixture was stirred for 2.5 hours at room temperature and concentratedto dryness under reduced pressure. Water was added to the residue, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and dried, and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel to afford the title compound as a colorless oil (0.44 g,76%).

¹ H-NMR(200 MHz,CDCl₃) δ: 0.91(3H,t), 1.28-1.46(2H,m), 1.63-1.78(2H,m),2.65(2H,t), 5.59(2H,s), 7.05(2H,d), 7.23(2H,d), 7.41-7.65(3H,m),7.90-7.95(1H,m), 9.77(1H,s).

IR(neat)cm⁻¹ : 2960, 1670, 1652, 1580, 1565, 1510.

22e) 2-Butyl-4-chloro-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5-formylimidazole

To a solution of the compound obtained in Working Example (22d) in amixture of dioxane (4 ml) and water (1 ml) was added 1N-NaOH (0.75 ml)under ice-cooling. The mixture was stirred for 30 minutes underice-cooling. To the reaction mixture were added 1N-HCl (1 ml) and water,followed by extraction with ethyl acetate. The organic layer was washedwith water and dried, and the solvent was evaporated under reducedpressure. The residue was recrystallized from isopropyl ether-hexane toafford the title compound as white crystals (0.225 g, 87%),m.p.181°-183° C.

Elemental Analysis for C₂₃ H₂₁ N₄ O₃ Cl.0.2H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   62.71;        4.90;  12.72    Found:    62.71;        4.79;  12.62    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.91(3H,t), 1.29-1.48(2H,m), 1.63-1.79(2H,m),2.68(2H,t), 5.55(2H,s), 7:10(2H,d), 7.31(2H,d), 7.38-7.67(3H,m),7.80(1H,dd), 8.50(1H,br), 9.68(1H,s).

IR(KBr)cm⁻¹ : 2960, 1772, 1673, 1522, 1490, 1460.

Working Example 23 2-Butyl-4-chloro1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5-hydroxymethylimidazole

To a solution of the compound (0.15 g) obtained in Working Example (22e)in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was addedsodium borohydride (16 mg), and the mixture was stirred for one hour atroom temperature. To the reaction mixture was added ice-water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and dried, and the solvent was evaporated in vacuo underreduced pressure. The residue was recrystallized from ether-hexane toafford the title compound as white crystals (67 mg, 45%), m.p.202°-205°C.

Elemental Analysis for C₂₃ H₂₃ N₄ O₃ Cl.0.1ET₂ O.0,5H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   61.73;        5.53;  12.30    Found:    61.81;        5.56;  12.07    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.80(3H,t), 1.16-1.34(2H,m),1.40-1.55(2H,m), 2.45-2.52(2H,m), 4.34-4.36(2H,m), 5.25(1H,br),5.29(2H,s), 7.14(2H,d), 7.30(2H,d), 7.48-7.72(4H,m).

IR(KBr)cm⁻¹ : 3470, 2960, 1755, 1501, 1463.

Working Example 24 5-Butyl-3-ethoxycarbonyl-1- 2'-(2,5-dihydro-5-oxo-1,24-oxadiazol-3-yl)biphenyl-4-yl!methylpyrazole

24a) 5-Butyl-3-ethoxycarbonyl-1-2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!pyrazole

To an ice-cooling solution of 3-butyl-5-ethoxycarbonylpyrazole (0.3 g)and the compound (0.95 g) obtained in Working Example (22c) in anhydroustetrahydrofuran (10 ml) was added sodium hydride (60%, 61 mg) undernitrogen atmosphere. The mixture was stirred for 10 minutes at roomtemperature, and then heated for 3 hours under reflux. The reactionmixture was cooled, to which was added water, followed by extractionwith ethyl acetate. The organic layer was washed with water and dried,and the solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel to afford the titlecompound as a pale yellow oil (0.29 g, 35%).

¹ H-NMR(200 MHz,CDCl₃) δ: 0.89(3H,t), 1.26-1.44(2H,m), 1.40(3H,t),1.50-1.68(2H,m), 2.49(2H,t), 4.41(2H,q), 5.41(2H,s), 6.64(1H,s),7.08(2H,d), 7.20(2H,d), 7.40-7.63(3H,m), 7.88-7.92(1H,m).

IR(neat)cm⁻¹ : 2950, 1715, 1578, 1565.

24b) 5-Butyl-3-ethoxycarbonyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxodiazol-3-yl)biphenyl-4-yl!methyl!pyrazole

To a solution of the compound (0.27 g) obtained in Working Example (24a)in a mixture of dioxane (4 ml) and water (1 ml) was added 1N-NaOH (0.6ml) under ice-cooling. The mixture was stirred for 20 minutes underice-cooling. To the reaction mixture were added 1N-HCl (0.9 ml) andwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water, dried, and concentrated to dryness underreduced pressure. The residue was recrystallized from isopropylether-hexane to afford the title compound as colorless crystals (0.176g, 80%), m.p.166°-168° C.

Elemental Analysis for C₂₅ H₂₆ N₄ O₄ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   67.25;        5.87;  12.55    Found:    66.99;        5.91;  12.45    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.91(3H,t), 1.28-1.46(2H,m), 1.37(3H,t),1.53-1.68(2H,m), 2.56(2H,t), 4.35(2H,q), 5.36(2H,s), 6.64(1H,s),7.15(2H,d), 7.30(2H,d), 7.37-7.65(3H,m), 7.79-7.83(1H,m), 8.49(1H,br).

IR(KBr)cm⁻¹ : 2960, 1777, 1725, 1600, 1485.

Working Example 25 2-Butyl-4-chloro-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!imidazole-5-carboxylicacid

To a solution of the compound (0.27 g) obtained in Working Example (22e)in pyridine (5 ml) was added an aqueous solution (2.5 ml) of potassiumpermanganate (0.147 g). The mixture was stirred for 3 hours at roomtemperature. The reaction mixture was concentrated to dryness underreduced pressure. To the residue were added ethyl acetate and dilutehydrochloric acid. The resulting suspension was filtrated throughcelite. The filtrate was extracted with ethyl acetate. The organic layerwas washed with water, dried, and concentrated to dryness under reducedpressure. The residue was purified by silica gel column chromatographyand the product was crystallized from ethyl acetate-isopropyl ether toafford the title compound as colorless crystals (0.17 g, 61%),m.p.188°-189° C. (decomp.).

Elemental Analysis for C₂₃ H₂₁ N₄ O₄ Cl.0.1AcOEt.2.9H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   54.69;        5.41;  10.90    Found:    54.91;        5.17;  10.62    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.80(3H,t), 1.16-1.35(2H,m),1.43-1.58(2H,m), 2.46-2.53(2H,m), 5.80(2H,s), 6.95(2H,d), 7.25(2H,d),7.29-7.51(4H,m).

IR(KBr)cm⁻¹ : 3390, 2960, 1765, 1648, 1590, 1525, 1488.

Working Example 26 2-Butyl-4-chloro-1-2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl!methyl!imidazole-5-carbaldehyde

To an ice-cooling solution of 2-butyl-4-chloroimidazole-5-carbaldehyde(0.19 g) in N,N-dimethylformamide (1 ml) was added sodium hydride (60%in oil; 44 mg), and the mixture was stirred for 10 minutes. To themixture was then added5-(4'-bromomethylbiphenyl-2-yl)-2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazol-2-one(0.57 g). The reaction mixture was stirred for 1.5 hour at roomtemperatures, which was diluted with water and extracted with ethylacetate. The extract was washed with water and dried. The solvent wasevaporated under reduced pressure, and the residue was purified bycolumn chromatography on silica gel. The crude product thus obtained wasdissolved in trifluoroacetic acid (4 ml), and the solution was stirredfor 30 minutes at 60° C. Trifluoroacetic acid was evaporated underreduced pressure. The residue was dissolved in ethyl acetate, and thesolution was washed with an aqueous solution of sodium hydrogencarbonateand dried. The solvent was evaporated under reduced pressure, and theresidue was purified by column chromatography on silica gel. Crudecrystals thus obtained was recrystallized from ethylacetate-hexane toafford the title compound as colorless prisms (0.12 g, 27%),m.p.178°-179° C.

Elemental Analysis for C₂₃ H₂₁ N₄ ClO₃ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   63.23;        4.84;  12.82    Found:    63.07;        4.87;  12.69    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.90(3H,t), 1.28-1.46(2H,m), 1.62-1.78(2H,m),2.68(2H,t), 5.59(2H,s), 7.08(2H,d), 7.26(2H,d), 7.35(1H,dd),7.43-7.60(2H,m), 7.79(1H,dd), 8.85(1H,br), 9.76(1H,s).

IR(neat)cm⁻¹ : 1810, 1775, 1660, 1455, 1340, 1275, 900, 840, 770, 750.

Working Example 27 2-Butyl-4-chloro-1-2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl!biphenyl-4-yl!methyl!-5-imidazolemethanol

To a solution of the compound (50 mg) obtained in Working Example 26 inmethanol (5 ml) was added sodium borohydride (4 mg), and the mixture wasstirred for one hour at 0° C. The solvent was evaporated under reducedpressure, and the residue was adjusted to pH 3-4 with 1N-HCl.Crystalline precipitate was collected by filtration and recrystallizedfrom ethyl acetate-hexane to afford the title compound as colorlessprisms (47 mg, 94%), m.p.163°-164° C.

Elemental Analysis for C₂₃ H₂₃ N₄ ClO₃ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   62.94;        5.28;  12.76    Found:    62.76;        5.16;  12.54    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.88(3H,t), 1.25-1.41(2H,m), 1.58-1.70(2H,m),2.62(2H,t), 4.50(2H,s), 5.24(2H,s), 7.06(2H,d), 7.27(2H,d), 7.37(1H,dd),7.43-7.59(2H,m), 7.81(1H,dd), 9.93(1H,br).

IR(KBr)cm⁻¹ : 3400, 1800, 1775, 1455, 1410, 1340, 1260, 1000, 900, 770,750.

Working Example 28 2-Butyl-5-ethoxycarbonyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4(3H)-pyrimidinone

28a) 2-Butyl-5-ethoxycarbonyl-3-2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4(3H)-pyrimidinone

To an ice-cooling solution of2-butyl-5-ethoxycarbonyl-4-hydroxypyrimidine (0.36 g) in anhydroustetrahydrofuran (8 ml) was added sodium hydride (60% in oil; 65 mg)under nitrogen atmosphere, and the mixture was stirred for 15 minutes atroom temperatures. To the reaction mixture was added a solution of thecompound (1.02 g) obtained in Working Example (22c) in anhydroustetrahydrofuran (5 ml), and the mixture was heated for 6 hours underreflux. The reaction mixture was cooled, to which was added water,followed by extraction with ethyl acetate. The organic layer was washedwith water and dried, and the solvent was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel to afford the title compound as a colorless oil (0.18 g, 20%).

¹ H-NMR(200 MHz,CDCl₃) δ: 0.92(3H,t), 1.29-1.47(2H,m), 1.39(3H,t),1.64-1.79(2H,m), 2.75(2H,t), 4.39(2H,q), 5.38(2H,s), 7.19(2H,d),7.25(2H,d), 7.41-7.65(3H,m), 7.93(1H,dd), 8.64(1H,s)

IR(neat)cm⁻¹ : 2960, 1748, 1705, 1685, 1580, 1521.

28b) 2-Butyl-5-ethoxycarbonyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4(3H)-pyrimidinone

The compound (0.18 g) obtained in Working Example (28a) was dissolved ina mixture of dioxane (4 ml) and water (1 ml). To the ice-coolingsolution was added 1N-NaOH (0.4 ml), and the reaction solution wasstirred for 30 minutes under ice-cooling. After addition of 1N-HCl (0.6ml) and water, the reaction mixture was extracted with ethyl acetate.The organic layer was washed with water and dried, and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel. The crude product thus obtained wasrecrystallized from ethyl acetate-isopropyl ether to afford the titlecompound as colorless crystals (62 mg, 42%), m.p.151°-154° C.

Elemental Analysis for C₂₆ H₂₆ N₄ O₅.0.1H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   65.56;        5.54;  11.76    Found:    65.41;        5.68;  11.62    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.91(3H,t), 1.28-1.48(2H,m), 1.34(3H,t),1.65-1.80(2H,m), 2.79(2H,t), 4.31(2H,q), 5.30(2H,s), 7.22(2H,d),7.32(2H,d), 7.37-7.65(3H,m), 7.78(1H,dd), 8.61(1H,s).

IR(KBr)cm⁻¹ : 3210, 2960, 1795, 1705, 1660, 1523.

Working Example 29 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-6-propoxy-3-propyluracil

29a) 6-Chloro-1-2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-3-propyluracil

To an ice-cooling solution of 6-chloro-3-propyluracil (0.2 g) inN,N-dimethylformamide (4 ml) was added sodium hydride (60% in oil; 43mg) under nitrogen atmosphere. The mixture was stirred for 30 minutes atthe same temperature. To the reaction mixture was added a solution ofthe compound (0.64 g) obtained in Working Example (22c) inN,N-dimethylformamide (4 ml). The mixture was stirred for 2.5 hours atroom temperature. The reaction mixture was concentrated to dryness underreduced pressure, and to the residue was added water, followed byextraction with ethyl acetate. The organic layer was washed with water,dried, and concentrated to dryness under reduced pressure. The residuewas purified by column chromatography on silica gel to afford the titlecompound as a colorless oil (0.43 g, 75%).

¹ H-NMR(200 MHz,CDCl₃) δ: 0.95(3H,t), 1.56-1.76(2H,m), 3.91(2H,t),5.29(2H,s), 5.93(1H,s), 7.24(2H,d), 7.31(2H,d), 7.43-7.64(3H,m),7.89-7.93(1H,m).

IR(neat)cm⁻¹ : 2960, 1712, 1668, 1608, 1582, 1568, 1508.

29b) 1-2'-(2,4-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl!methyl!-6-propoxy-3-propyluracil

To a solution of the compound (0.42 g) obtained in Working Example (29a)in a mixture of dioxane (4 ml) and water (1 ml) was added 1N-NaOH (1.0ml) under ice-cooling. The mixture was stirred for 30 minutes underice-cooling, and to the reaction mixture were added 1N-HCl (1.5 ml) andwater, followed by extraction with ethyl acetate. The organic layer waswashed with water, dried, and concentrated to dryness under reducedpressure. The residue was dissolved in a mixture of propanol (4 ml) andN,N-dimethylformamide (4 ml). To the ice-cooling solution were addeddropwise a solution of sodium propoxide prepared from metallic sodium(72 mg) and propanol (2 ml), and the solution was heated for 1.5 hour at100°-110° C. The reaction mixture was cooled, and then concentrated todryness under reduced pressure. To the residue was added dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, dried, and evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography on silica gel. The crude product thus obtained wasrecrystallized from ethyl acetate-hexane to afford the title compound ascolorless crystals (0.223 g, 63%), m.p.129°-132° C.

Elemental Analysis for C₂₅ H₂₆ N₄ O₅ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   64.92;        5.67;  12.11    Found:    64.82;        5.77;  11.91    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.92(3H,t), 1.00(3H,t), 1.56-1.73(2H,m),1.74-1.93(2H,m), 3.85(2H,t), 3.98(2H,t), 5.11(2H,s), 5.15(1H,s),7.28-7.67(7H,m), 7.81-7.86(1H,m), 8.15(1H,br s).

IR(KBr)cm⁻¹ : 3120, 2970, 1775, 1705, 1638, 1472.

Working Example 30 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylbenzimidazole-7-carboxylicacid

30a) Methyl 1- (2'-cyanobiphenyl-4-yl)methyl!-2-propylbenzimidazole-7-carboxylate

To a solution of methyl 3-amino-2-(2'-cyanobiphenyl-4-yl)methyl!benzoate (1.43 g) in dioxane (8 ml) wasadded butyric anhydride (950 mg), and the mixture was stirred for 3hours at room temperature, and then for two hours at 110° C. To thereaction mixture was added conc. HCl (1 ml), and the mixture was stirredfor 15 hours at 80° C. The reaction mixture was partitioned betweenethyl acetate (150 ml) and an aqueous solution of sodiumhydrogencarbonate (70 ml). The upper layer was washed twice with water(50 ml) and concentrated under reduced pressure. The crystalline productwas recrystallized from ethyl acetate-ether to afford the title compoundas colorless prisms (1.4 g, 85%), m.p.128°-129° C.

⁻¹ H-NMR(90 MHz,CDCl₃) δ: 1.10(3H,t), 1.77-2.10(2H,m), 2.87(3H,t),3.67(3H,s), 5.77(2H,s), 6.93(2H,d), 7.13-7.77(8H,m), 7.93(1H,d).

IR(Nujol)cm⁻¹ : 2225, 1710, 1450, 1280, 1270, 1200, 1130, 760.

30b) Methyl 1-(2'-(hydroxycarbamimidoyl)biphenyl-4-yl)methyl!-2-propylbenzimidazole-7-carboxylate

To a solution of hydroxylamine hydrochloride (2.78 g) in DMSO (12 ml)was added triethylamine (4.04 g) and tetrahydrofuran (15 ml), and thenthe resulting crystals were filtered off. The filtrate was concentratedto dryness under reduced pressure. To the residue were added methyl 1-(2'-cyanobiphenyl-4-yl)methyl!-2-propylbenzimidazole-7-carboxylate (1.6g) and triethylamine (1 g). The mixture was stirred for 15 hours at 75°C., which was then dissolved in ethyl acetate (200 ml). The solution waswashed with water (200 ml and 50 ml×3), dried and evaporated underreduced pressure to afford the title compound as a pale yellow product(1.57 g, 89%).

¹ H-NMR(90 MHz,CDCl₃) δ: 1.10(3H,t), 1.73-2.10(2H,m), 2.90(2H,t),3.70(3H,s), 4.33(2H,broad), 5.73(2H,s), 6.87(2H,d), 7.10-7.67(8H,m),7.93(1H,d).

IR(Nujol)cm⁻¹ : 1720, 1440, 1380, 1290, 1265.

30c) Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylbenzimidazol-7-carboxylate

To a solution of methyl 1-(2'-N-hydroxyamidino-biphenyl-4-yl)methyl!-2-propylbenzimidazole-7-carboxylate(1.5 g) in DMF (8 ml) was added pyridine (240 mg) and chloroformic acid2-ethylhexyl ester (556 mg) with stirring in an ice-bath. The mixturewas stirred for 0.5 hour under the same conditions, to which was addedmethanol (3 ml), and the mixture was stirred for 0.5 hour at roomtemperature. The reaction mixture was dissolved in ethyl acetate (250ml), and the solution was washed with water (200 ml and 50 ml×3). Ethylacetate was evaporated under reduced pressure. The residue was dissolvedin xylene (150 ml), and the solution was heated for 4 hours underreflux. The reaction mixture was allowed to stand for 20 hours at roomtemperature to give the title compound as colorless prisms (1.03 g,58%), m.p.224°-226° C.

Elemental Analysis for C₂₇ H₂₄ N₄ O₄.1/2C₈ H₁₀ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   71.46;        5.60;  10.74    Found:    71.41;        5.44;  10.53    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 0.90(3H,t), 1.13-1.73(2H,m), 2.43(2H,t),3.57(3H,s), 5.57(2H,s), 6.50-7.93(11H,m).

IR(Nujol) cm⁻¹ : 1770, 1720, 1267.

30d) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylbenzimidazole-7-carboxylicacid

A mixture of methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylbenzimidazole-7-carboxylate(703 mg) in 0.3N-NaOH (12 ml) was stirred at 60° C. for one hour, andthen adjusted to pH 3 with 0.1N-HCl. Resulting precipitates wereextracted with a mixture of chloroform-ethanol (10:1; 150 ml). Thesolvent was evaporated under reduced pressure, and the residue wascrystallized from methanol to give the title compound as colorlessprisms (550 mg, 90%), m.p.169°-171° C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₄ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   67.38;        5.00;  12.09    Found:    67.39;        4.85;  11.91    ______________________________________

¹ H-NMR(90 MHz,DMSOd₆ -CDCl₃) δ: 1.03(3H,t), 1.67-2.10(2H,m),2.83(2H,t), 5.97(2H,s), 7.00(2H,d), 7.20-8.03(9H,m).

IT(Nujol)cm⁻¹ : 1785, 1710, 1500, 1380, 760.

Working Example 31 2-Ethyl-1-(2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

31a) Methyl 1-(2'-cyanobiphenyl-4-yl)methyl!-2-ethylbenzimidazole-7-carboxylate

Methyl 3-amino-2- (2'-cyanobiphenyl-4-yl)methyl!-benzoate (1.79 g) wastreated with propionic anhydride (1.04 g) in the similar manner asWorking Example (30a). The product was recrystallized from ethyl acetateto give the title compound as colorless prisms (1.5 g, 76%), 153°-154°C.

¹ H-NMR(90 MHz,CDCl₃) δ: 1.47(3H,t), 2.90(2H,q), 3.73(3H,s), 5.83(2H,s),6.97(2H,d), 7.30-7.83(8H,m), 7.97(1H,d).

IR(Nujol)cm⁻¹ : 2225, 1725, 1710, 1480, 1440, 1285, 1250, 1205, 1120.

31b) Methyl 2-ethyl-1- (2'-(hydroxycarbamimidoyl)biphenyl-4-yl)methyl!benzimidazole-7-carboxylate

Methyl 1-(2'-cyanobiphenyl-4-yl)methyl!-2-ethylbenzimidazole-7-carboxylate (2 g)was subjected to the similar reaction as in Working Example (30b) togive the title compound as a pale yellow resinous substance (1.85 g,85%).

¹ H-NMR(90 MHz,CDCl₃) δ: 1.43(3H,t), 2.97(2H,q), 3.73(3H,s),4.40(2H,broad), 5.73(2H,s), 6.90(2H,d), 7.17-7.80(8H,m), 7.97(1H,d).

IR(Nujol)cm⁻¹ : 1720, 1380, 1290, 1265.

Working Example 32 2-Cyclopropyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

32a) Methyl 1(2'-cyanobiphenyl-4-yl)methyl!-2-cyclopropylbenzimidazole-7-carboxylate

Methyl 3-amino-2- (2'-cyanobiphenyl-4-yl)methyl!benzoate (1.79 g) wastreated with cyclopropane-carboxylic anhydride (1.3 g) in the similarmanner as in Working Example (30a) to give the title compound as anorange syrup (1.85 g, 91%).

¹ H-NMR(90 MHz,CDCl₃) δ: 1.00-1.40(4H,m), 1.87-2.23(1H,m), 3.70(3H,s),5.93(2H,s), 7.00-7:93(11H,m).

IR(Neat)cm⁻¹ : 2225, 1720, 1710, 1525, 1440, 1285.

32b) Methyl 2-cyclopropyl-1-(2'-(hydroxycarbamimidoyl)biphenyl-4-yl)methyl!benzimidazole-7-carboxylate

Methyl 1-(2'-cyanobiphenyl-4-yl)methyl!-2-cyclopropylbenzimidazole-7-carboxylate(1.8 g) was subjected to the similar reaction as in Working Example(32b) to give the title compound as a pale yellow syrup (1.75 g, 90%).

¹ H-NMR(90 MHz,CDCl₃) δ: 0.97-1.43(4H,m), 1.80-2.17(1H,m), 3.70(3H,s),4.33(2H,broad), 5.87(2H,s), 6.87(2H,d), 7.10-7.63(8H,m), 7.87(1H,d).

IR(Nujol)cm⁻¹ : 1720, 1440, 1380, 1290, 1265, 760.

32c) Methyl 2-cyclopropyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

Methyl 2-cyclopropyl-1-(2'-N-hydroxyimino-carboxamidebiphenyl-4-yl)methyl!benzimidazole-7-carboxylate(1.7 g) was subjected to the similar reaction as in Working Example(30c). From the reaction mixture, xylene was evaporated under reducedpressure. The residue was recrystallized from ethyl acetate to give thetitle compound as colorless prisms (780 mg, 48%), m.p.188°-190° C.

Elemental Analysis for C₂₇ H₂₂ N₄ O₄ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   69.52;        4.75;  12.01    Found:    69.52;        4.77;  11.90    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 0.87-1.07(4H,m), 1.53-1.80(1H,m), 3.73(3H,s),5.87(2H,s), 6.83-7.87(11H,m).

IR(Nujol)cm⁻¹ : 1778, 1765, 1728, 1716, 1211.

32d) 2-Cyclopropyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

Methyl 2-cyclopropyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate(550 mg) was subjected to the similar reaction as in Working Example(30d). The product was recrystallized from ethyl acetate to give thetitle compound as colorless prisms (480 mg, 90%), m.p.199°-200° C.

Elemental Analysis for C₂₈ H₂₀ N₄ O₄.1/3H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   68.11;        4.54;  12.22    Found:    68.16;        4.61;  12.03    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 0.93-1.30(4H,m), 2.07-2.40(1H,m), 6.07(2H,s),7.00-7.83(11H,m), 12.27(1H,broad).

IR(Nujol)cm⁻¹ : 1755, 1703, 1699, 1257.

Working Example 33 2-Butyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

The methyl ester (0.53 g) obtained in Working Example 2 was subjected tothe similar reaction as in Working Example (30d) to give the titlecompound as colorless prisms (0.36 g, 64%), m.p.165°-167° C.

Elemental Analysis for C₂₇ H₂₄ N₄ O₄.1/3CHCl₃ :

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   64.59;        4.83;  11.02    Found:    64.76;        4.95;  10.83    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 0.90(3H,t), 1.13-2.00(4H,m), 2.83(2H,t),5.93(2H,s), 6.93(2H,d), 7.13-7.90(9H,m).

IR(Nujol)cm⁻¹ : 1770, 1700, 1440, 1420, 1250, 765.

Working Example 34 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylthiobenzimidazole-7-carboxylicacid

34a) Methyl2-(2'-cyanobiphenyl-4-yl)methylamino-3-methoxycarbonylaminobenzoate

To an ice-cooling solution of the compound (10.0 g) obtained in WorkingExample (1a) in pyridine (50 ml) was added dropwise methyl chloroformate(9.0 ml), and the mixture was stirred for 3 hours at room temperature.The reaction mixture was concentrated to dryness, and to the residue wasadded water. After extraction with ethyl acetate, the extract was washedwith water, dried and concentrated to dryness. The residue wascrystallized from ethyl acetate-hexane to afford pale yellow crystals(10.5 g, 90%), m.p.113°-115° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 3.80(3H,s), 3.83(3H,s), 4.11(2H,d), 6.29(1H,brs), 7.09(1H,t), 7.40-7.80(10H,m), 8.19(1H,d).

34b) Methyl 1- (2'-cyanobiphenyl-4-yl)methyl!-2,3-dihydro-2-oxobenzimidazole-7-carboxylate

To a suspension of the compound (10.5 g) obtained in Working Example(34a) in methanol (100 ml) was added a solution of 28% sodium methoxidein methanol (10 g). The mixture was heated for 21 hours under reflux.The reaction mixture was adjusted to pH 3 with 1N-HCl and concentratedto dryness. After addition of water to the residue, the mixture wasextracted with chloroform. The extract was dried and concentrated todryness. The residue was crystallized from chloroform-methanol to givecolorless needles (8.7 g, 90%), m.p.250°-253° C.

¹ H-NMR(200 MHz,DMSO-d₆) δ: 3.65(3H,s), 5.35(2H,s), 7.04-7.16(3H,m),7.24-7.28(2H,m), 7.48-7.59(4H,m), 7.76(1H,dt), 7.92(1H,dd).

IR(KBr)cm⁻¹ : 2210, 1720, 1690, 1635, 1430, 1390, 1270, 1255, 760, 750,730, 690.

34c) Methyl 1-(2'-cyanobiphenyl-4-yl)methyl!2-propylthiobenzimidazole-7-carboxylate

A mixture of the compound (11 g) obtained in Working Example (34b) inphosphorus oxychloride (90 g) was heated for 10 hours under reflux,followed by conventional workup to give methyl2-chloro-1-(2'-cyanobiphenyl-4-yl)methylbenzimidazole-7-carboxylate(11.37 g). To a solution of the compound in dioxane (100 ml) was addedpropyl mercaptane (2.4 g) and a 28% solution of sodium methoxide inmethanol (6.4 g). The mixture was stirred for 1.5 hour at roomtemperature. The reaction mixture was concentrated to dryness underreduced pressure. The residue was partitioned between ethyl acetate (300ml) and water (150 ml), and then the upper layer was washed with water(50 ml×1). Ethyl acetate was evaporated under reduced pressure. Afteraddition of methanol (50 ml) to the residue, the resulting crystallineprecipitate was collected by filtration, washed with methanol and driedto afford the title compound as pale yellow prisms (10 g, 80%),m.p.107°-108° C.

¹ H-NMR(90 MHz,CDCl₃) δ: 1.07(3H,t), 1.63-2.03(2H,m), 3.40(2H,t),3.73(3H,s), 5.80(2H,s), 7.00-7.93(11H,m).

IR(Nujol)cm⁻¹ : 2220, 1725, 1280.

34d) Methyl 1-(2'-(hydroxycarbamimidoyl)biphenyl-4-yl)methyl!-2-propylthiobenzimidazole-7-carboxylate

To a solution of hydroxylamine hydrochloride (20.85 g) in DMSO (200 ml)was added triethylamine (3.9 g) and the mixture was stirred for 30minutes at room temperatures. To the reaction mixture was added thecompound (16 g) obtained in Example (34c), and the mixture was stirredfor 60 hours at 70° C. To the resultant mixture was addedtetrahydrofuran (100 ml). After removal of crystalline precipitate byfiltration, the filtrate was concentrated to dryness. The residue waspartitioned between water (1.2 liter) and ethyl acetate (350 ml), andthe upper layer was washed with water (70 ml×3). Ethyl acetate wasevaporated under reduced pressure, and to the residue was added methanol(70 ml). Resulting crystalline precipitate was filtered off. Thefiltrate was concentrated to dryness under reduced pressure to give thetitle compound as a pale yellow syrup (13.0 g, 76%).

¹ H-NMR(90 MHz,CDCl₃) δ: 1.07(3H,t), 1.63-2.03(2H,m), 3.40(2H,t),3.73(3H,s), 4.37(2H,broad), 5.13(1H,broad), 5.73(2H,s), 6.97(2H,d),7.10-7.60(8H,m), 7.87(2H,d).

IR(Nujol)cm⁻¹ : 1720, 1645, 1280, 755.

34e) Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylthiobenzimidazole-7-carboxylate

To a stirred solution of the compound (13.0 g) obtained in WorkingExample (34d) in DMF (20 ml) were added pyridine (2.2 g) and2-ethylhexyl chloroformate (4.83 g) successively under cooling with anice-bath. The mixture was stirred for 30 minutes under the sameconditions, to which was added methanol (5 ml), followed by stirring for30 minutes at room temperatures. The reaction mixture was partitionedbetween ethyl acetate (250 ml) and water (250 ml). The upper layer waswashed with water (150 ml×3) and concentrated to dryness under reducedpressure. The residue was dissolved in xylene (180 ml), and the solutionwas stirred for 70 minutes on a bath of 160° C. The solution wasconcentrated to dryness under reduced pressure. To the residue was addedmethanol (70 ml) to give the title compound as pale yellow prisms (7.16g, 57%), m.p.220°-221° C.

Elemental Analysis for C₂₇ H₂₄ N₄ O₄ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   64.78;        4.83;  11.19    Found:    64.54;        4.92;  10.89    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.03(3H,t), 1.60-2.00(2H,m), 3.27(2H,t),3.73(3H,s), 5.73(2H,s), 6.90-7.87(11H,m).

IR(Nujol)cm⁻¹ : 1760, 1720, 1280, 1260.

34f) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylthiobenzimidazole-7-carboxylicacid

To a solution of the compound (0.3 g) obtained in Working Example (34e)in tetrahydrofuran (10 ml) were added 2N-NaOH (2 ml) and methanol (5ml). The mixture was stirred for 3 hours at 80° C. The reaction mixturewas concentrated under reduced pressure. To the residue was added water(20 ml), and the aqueous solution was adjusted to pH 3 with 2N-HCl.Precipitates then formed were collected by filtration and recrystallizedfrom ethyl acetate to give colorless prisms (0.19 g, 65%), m.p.228°-229°C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₄ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   64.18;        4.56;  11.52    Found:    64.15;        4.62;  11.56    ______________________________________

¹ H-NMR(90 MHz,CDCl₃ --CD₃ OD) δ: 1.07(3H,t), 1.63-2.03(2H,m),3.37(2H,t), 5.87(2H,s), 6.97-7.90(11H,m).

IR(Nujol)cm⁻¹ : 1795, 1700, 1455, 1280, 1240, 755.

Working Example 35 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxybenzimidazole-7-carboxylicacid

35a) Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylsulfinylbenzimidazole-7-carboxylate

To a stirred solution of the compound (2.5 g) obtained in WorkingExample (34e) in dichloromethane (60 ml) was added metachloroperbenzoicacid (1.1 g) in portions under cooling with an ice-bath. The mixture wasstirred for one hour under the same conditions, which was washed with asolution of sodium hydrogencarbonate (500 mg) in water (50 ml). Theorganic layer was washed with water (30 ml×1) and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure toafford the title compound as a pale yellow syrup (2.58 g, 100%).

¹ H-NMR(90 MHz,CDCl₃) δ: 1.03(3H,t), 1.57-2.00(2H,m), 3.13-3.63(2H,m),3.77(3H,s), 6.07(1H,d), 6.17(1H,d), 6.93(2H,d), 7.17-8.03(9H,m).

IR(Nujol)cm⁻¹ : 1780, 1720, 1285, 1260, 755.

35b) Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxybenzimidazole-7-carboxylate

To a solution of the compound (517 mg) obtained in Working Example (35a)in methanol (5 ml) was added a solution of 28% sodium methoxide inmethanol solution (579 mg), and the mixture was allowed to stand for onehour at room temperature. To the mixture was added 2N--HCl to adjust topH 3, and the mixture was concentrated under reduced pressure. Theresidue was partitioned between water (20 ml) and dichloromethane (50ml). The organic layer was concentrated to dryness under reducedpressure, and the residue was crystallized from methanol to afford thetitle compound as prisms (308 mg, 68%), m.p.215°-216° C.

Elemental Analysis for C₂₅ H₂₀ N₄ O₅.0.1H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   65.53;        4.44;  12.23    Found:    65.38;        4.56;  12.12    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 3.73(3H,s), 4.27(3H,s), 5.63(2H,s),7.03(2H,d), 7.20-7.77(9H,m).

IR(Nujol)cm⁻¹ : 1760, 1720, 1560, 1435, 1405, 1285, 1250, 1040, 740.

35c) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxybenzimidazole-7-carboxylicacid

The compound (228 mg) obtained in Working Example (35b) was subjected tothe similar reaction as in Working Example (34f), and the product wasrecrystallized from ethyl acetate to give the title compound ascolorless prisms (133 mg, 60%), m.p.189°-190° C.

Elemental Analysis for C₂₄ H₁₈ N₄ O₅.0.75H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   63.22;        4.31;  12.29    Found:    63.50;        4.28;  12.03    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 4.20(3H,s), 5.73(2H,s), 7.03-7.73(11H,s),12.17(1H,broad), 12.93(1H,broad).

IR(Nujol)cm⁻¹ : 1780, 1705, 1560, 1415, 1250, 1040.

Working Example 36 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propoxybenzimidazole-7-carboxylicacid

36a) Methyl 1-2-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propoxybenzimidazole-7-carboxylate

A solution of 28% sodium methoxide in methanol (710 mg) was concentratedto dryness under reduced pressure, and the residue was dissolved inpropanol (10 ml). In the solution was dissolved the compound (517 mg)obtained in Working Example (35a), and the solution was allowed to standfor two hours at room temperature. The solution was adjusted to pH 3with 2N-HCl and concentrated to dryness under reduced pressure. Theresidue was dissolved in methanol (15 ml), and to the solution was addeda solution of 28% sodium methoxide in methanol (710 mg). The mixture wasallowed to stand for 15 hours at room temperature and adjusted to pH 3with 2N-HCl, followed by concentration under reduced pressure. Theresidue was partitioned between water (25 ml) and dichloromethane (25ml). The organic layer was concentrated to dryness under reducedpressure. The residue was crystallized from methanol to give the titlecompound colorless prisms (310 mg, 64%), m.p.172°-174° C.

Elemental Analysis for C₂₇ H₂₄ N₄ O₅.0.2H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   66.44;        5.04;  11.48    Found:    66.57;        5.01;  11.55    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.00(3H,t), 1.60-2.00(2H,m), 3.63(3H,s),4.23(2H,t), 5.60(2H,s), 6.80-7.93(11H,m).

IR(Nujol)cm⁻¹ : 1780, 1720, 1550, 1440, 1280, 755.

36b) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propoxybenzimidazole-7-carboxylicacid

The compound (194 mg) obtained in Working Example (36a) was subjected tothe similar reaction as in Working Example (34f), and the product wasrecrystallized from ethyl acetate to give the title compound ascolorless prisms (132 mg, 70%), m.p.170°-172° C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₅.H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   63.93;        4.95;  11.47    Found:    63.82;        4.65;  11.41    ______________________________________

¹ H-NMR(90 MHz,CDCl₃ --CD₃ OD) δ: 1.00(3H,t), 1.67-2.07(2H,m),4.50(2H,t), 5.67(2H,s), 7.00-7.80(11H,m).

IR(Nujol)cm⁻¹ : 1765, 1725, 1550, 1430.

Working Example 37 2-Ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

37a) Methyl 2-ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

To a solution of the compound (517 mg) obtained in Working Example (35a)in methanol (3 ml) were added triethylamine (404 mg) and ethyl mercaptan(186 mg). The mixture was allowed to stand for 60 hours at roomtemperature and concentrated to dryness in vacuo. After addition ofwater (20 ml) to the residue, the mixture was adjusted to pH 3 with2N-HCl. The solution was extracted with ethyl acetate (60 ml). The upperlayer was washed with water (10 ml×3), and then concentrated to drynessin vacuo. The residue was crystallized from ethyl acetate to give thetitle compound as colorless prisms (370 mg, 76%), m.p.210°-211° C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₄ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   64.18;        4.56;  11.52    Found:    64.06;        4.58;  11.40    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.40(3H,t), 3.27(2H,q), 3.70(3H,s), 5.70(2H,s),6.87-7.87(11H,m).

IR(Nujol)cm⁻¹ : 1760, 1720, 1280, 1260.

37b) 2-Ethylthio-1- 2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylic acid

The compound (260 mg) obtained in Working Example (37a) was subjected tothe similar reaction as in Working Example (34f), and the product wasrecrystallized from methanol-water to afford the title compound ascolorless needles (160 mg, 63%), m.p.146°-148° C.

Elemental Analysis for C₂₅ H₂₀ N₄ O₄ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   63.55;        4.27;  11.86    Found:    63.28;        4.37;  11.59    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.43(3H,t), 3.40(2H,q), 5.70(2H,s),6.90-7.87(11H,m).

IR(Nujol)cm⁻¹ : 1785, 1765, 1700, 1350, 760.

Working Example 38 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylthiobenzimidazole-7-carboxylicacid

38a) Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylthiobenzimidazole-7-carboxylate

The compound (690 mg) obtained in Working Example (35a) was subjected tothe similar reaction as in Working Example (37a), and the product wasrecrystallized from methanol to afford the title compound as colorlessprisms (460 mg, 73%), m.p.231°-232° C.

Elemental Analysis for C₂₅ H₂₀ N₄ O₄ S:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   63.55;        4.27;  11.86    Found:    63.36;        4.33;  11.76    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 2.77(3H,s), 3.73(3H,s), 5.73(2H,s),7.00-7.93(11H,m), 12.33(1H,broad).

IR(Nujol)cm⁻¹ : 1760, 1710, 1430, 1270, 1250, 760.

38b) 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylthiobenzimidazole-7-carboxylicacid

The compound (360 mg) obtained in Working Example (38a) was subjected tothe similar reaction as in Working Example (34f), and the product wasrecrystallized from methanol to afford the title compound as colorlessprisms (270 mg, 77%), m.p.222°-223° C.

Elemental Analysis for C₂₄ H₁₈ N₄ S.0.8H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   60.95;        4.18;  11.85    Found:    60.83;        4.40;  11.58    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 2.77(3H,s), 5.83(2H,s), 7.00-7.77(11H,m),12.60(2H,broad).

IR(Nujol)cm⁻¹ : 1760, 1270, 760.

Working Example 39 Dipotassium salt of 2-Ethoxy-1-2'-(5-oxide-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

A solution of 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid (456 mg) in 0.2N--KOH (10 ml) was concentrated to dryness underreduced pressure. To the residue was added acetone (30 ml), and themixture was stirred for three days at room temperature. Crystals thenprecipitated were collected by filtration and dried (120° C., 1.5 hour)to give the title compound as colorless needles (470 mg, 89%),m.p.245°-247° C.

Elemental Analysis for C₂₅ H₁₈ N₄ O₅ K₂.3/2H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   53.65;        3.78;  10.01    Found:    53.77;        3.63;  9.93    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 1.40(3H,t), 4.53(2H,q), 5.83(2H,s),6.90-7.70(11H,m).

IR(Nujol)cm⁻¹ : 3370, 1660, 1610, 1570, 1540, 1385.

Working Example 40 Disodium salt of 2-ethoxy-1-2'-(5-oxide-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

In ethanol (500 ml) was dissolved a solution of 28% sodium methoxide inmethanol (43.7 g), and the solution was concentrated to dryness underreduced pressure. To the residue were added ethanol (500 ml) and2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid (52.5 g), and the mixture was dissolved. The solution wasconcentrated to dryness under reduced pressure. The residue wasdissolved in ethanol (250 ml) by heating, and then the solution wasallowed to stand for 40 hours at room temperature. Crystals thenprecipitated were collected by filtration, washed with ethanol (30 ml)and dried (140° C., 2 hours) to give colorless prisms (35.5 g), whichwere allowed to stand for three days in the air at room temperature toafford the titled compound as colorless prisms (42.34 g, 61%),m.p.294°-297° C.

Elemental Analysis for C₂₅ H₁₈ N₄ O₅ Na₂.5.5H₂ O:

    ______________________________________            C(%)        H(%)   N(%)    ______________________________________    Calcd.:   50.09;        4.88;  9.35    Found:    50.32;        4.71;  9.21    ______________________________________

¹ H-NMR(90 MHz,DMSO-d₆) δ: 1.43(3H,t), 4.57(2H,q), 5.80(2H,s),6.87-7.63(11H,m).

IR(Nujol)cm⁻¹ : 3375, 1655, 1615, 1410, 1350, 1280, 1040, 770.

Working Example 41 Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

41a) Methyl 1,3-dihydro-4-methyl-2-oxo-thieno3,4-d!imidazole-6-carboxylate

Methyl 3,4-diamino-5-methylthiophene-2-carboxylate (3.0 g) was dissolvedin a mixture of N,N-dimethyl formamide (5 ml) and dichloromethane (15ml). To the solution was added triphosgene (2.4 g) in portions. Themixture was stirred for two days at room temperature, and precipitateswere collected by filtration, washed with dichloromethane and dried.Resultant white powder (2.4 g) was suspended in N,N-dimethylformamide(25 ml). To the suspension was added sodium hydride (60% in oil; 0.55g), and the mixture was stirred for three days at room temperature. Thesolvent was evaporated under reduced pressure. To the residue was added2N-HCl. Resulting precipitates were collected by filtration, washed withwater, ether and methanol successively, followed by drying to afford thetitle compound (82 g, 53%) as pale brown powder.

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.32(3H,s), 3.73(3H,s), 10.71(1H,bs),11.06(1H,bs).

IR(KBr)cm⁻¹ : 3300, 1735, 1675, 1585, 1440.

41b) Methyl 2-ethoxy-4-methylthieno 3,4-d!imidazole-6-carboxylate

The compound (1.0 g) obtained in Working Example (41a) was suspended ina mixture of dioxane (10 ml) and dichloromethane (20 ml). To thesuspension was added an excess amount of triethyl oxoniumtetrafluoroborate at room temperatures in nitrogen atmosphere, and themixture was stirred for 19 hours. The reaction mixture was poured intoice-water, and the mixture was extracted four times with a mixture ofchloroform and ethanol. Organic layers were combined, dried, andconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography on silica gel to afford the title compound (945mg, 75%) as pale yellow powder, m.p.209°-210° C.

Elemental Analysis for C₁₀ H₁₂ N₂ O₃ S.0.2H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  49.25;        5.12;   11.49    Found:   49.42;        4.95;   11.29    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.44(3H,t), 2.57(3H,s), 3.87(3H,s),4.54(2H,q), 9.03(1H,bs).

IR(KBr)cm⁻¹ : 3250, 1670, 1640, 1580, 1540.

41c) Methyl 2-ethoxy-1- 2'-(5-trichloromethyl-1,2,4-oxadiazo-3-ylbiphenyl-4-yl!methyl!-4-methylthieno 3,4-d!imidazole-6-carboxylate

The compound (100 mg) obtained in Working Example (41b) and4'-bromomethyl-2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl (193mg) were dissolved in N,N-dimethyl formamide (3.5 ml). To theice-cooling solution was added sodium hydride (60% in oil; 18 mg) undernitrogen atmosphere. The mixture was stirred for 15 minutes underice-cooling, then for one hour at room temperature. The reaction mixturewas diluted with ethyl acetate, and the solution was washed with dilutehydrochloric acid, water and an aqueous saline solution, successively,followed by drying: The solvent was evaporated under reduced pressure.The residue was purified by column chromatography on silica gel toafford the title compound (121 mg, 55%) as a pale yellow oil.

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.55(3H,s), 3.79(3H,s),4.52(2H,q), 5.57(2H,s), 7.15(2H,d), 7.23(2H,d), 7.86(1H,d).

IR(neat)cm⁻¹ : 1690, 1615, 1570, 1535.

41d) Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

The compound (120 mg) obtained in Working Example (41c) was dissolved ina mixture of dioxane (4 ml) and water (1 ml). To the ice-coolingsolution was added 1N-NaOH (0.26 ml), and the mixture was stirred for 50minutes at the same temperature. The reaction mixture was made acid-with2N-HCl and extracted with ethyl acetate. The extract was washed withwater and dried, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give a yellow oil. The product was crystallized from ether and hexaneto afford the title compound (81 mg, 77%) as pale yellow crystals,m.p.208°-210° C.

Elemental Analysis for C₂₅ H₂₂ N₄ O₅ S:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  61.21;        4.52;   11.42    Found:   60.98;        4.55;   11.27    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.42(3H,s), 3.74(3H,s),4.42(2H,q), 5.58(2H,s), 7.2-7.7(7H,m), 7.82(1H,dd), 7.68(1H,bs).

IR(KBr)cm⁻¹ : 1760, 1700, 1620, 1580, 1535.

Working Example 42 Disodium salt of 1-2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid

The compound (0.5 g) obtained in Working Example 9 was suspended inmethanol (10 ml). To the suspension was added an aqueous solution (5 ml)of sodium hydroxide (90 mg), and the mixture was stirred for 10 minutesat room temperature. The reaction solution was concentrated to drynessto give crude crystals. Recrystallization from ethanol-ether affordedthe title compound as pale yellow crystals (0.28 g, 49%), 263°-266° C.(decomp.).

Elemental Analysis for C₂₃ H₁₆ N₄ O₅ SNa₂.1.0H₂ O (molecular weight524.46):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  52.67;        3.46;   10.68    Found:   52.88;        3.43;   10.45    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.37(3H,s), 4.00(3H,s), 5.80(2H,s),7.16-7.50(8H,m).

IR(KBr)cm⁻¹ : 1680, 1620, 1575, 1545, 1460, 1395, 1360.

Working Example 43 2-Ethylthio-1-3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

43a) 4'-Methyl-3-cyanobiphenyl

This compound was synthesized according to the procedure described inthe literature (Y. Hamana, S. Fukushima & T. Hiyama, Chem. Lett., 1989,1711).

M.p.71°-73° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 7.28(2H,d), 7.46(2H,d),7.51(1H,t), 7.60(1H,td), 7.79(1H,td), 7.84(1H,t).

IR(KBr)cm⁻¹ : 2230, 1475, 825, 800.

43b) 4'-Methylbiphenyl-3-carboxamide oxime

To a solution of hydroxylamine hydrochloride (2.61 g) in DMSO (20 ml)was added a solution of 28% NaOMe in methanol (7.25 g), and the mixturewas stirred for 10 minutes at room temperature. To the reaction mixturewas added the solution of the compound (1.45 g) obtained in WorkingExample (43a) in DMSO (10 ml). The mixture was stirred for one hour at100° C. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The extract was washed with water anddried. The solvent was evaporated in vacuo, and the residue was purifiedby column chromatography on silica gel to afford colorless crystals(1.30 g, 76.6%), m.p.134°-136° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.39(3H,s), 4.93(2H,br s), 7.25(2H,d),7.41-7.66(5H,m), 7.85(1H,t).

IR(KBr)cm⁻¹ : 3495, 3385, 1660, 1585, 1440, 1375, 940, 925, 900, 795.

43c) 5-Trichloromethyl-3-(4'-methylbiphenyl-3-yl)-1,2,4-oxadiazole

To a suspension of the compound (1.30 g) obtained in Working Example(43b) in toluene (30 ml) was added trichloroacetic anhydride (2.13 g).The mixture was stirred for 30 minutes at 80° C. The reaction mixturewas concentrated to dryness, and the residue was partitioned betweenethyl acetate and water. The organic layer was dried over Na₂ SO₄ andconcentrated to dryness. The residue was purified by columnchromatography on silica gel to afford a colorless oil (2.09 g,quantitatively).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 7.28(2H,d), 7.55(2H,d),7.56(1H,t), 7.76(1H,td), 8.07(1H,td), 8.32(1H,t).

IR(Neat)cm⁻¹ : 1570, 1515, 1460, 1355, 1335, 850, 825, 800, 745, 690.

43d) 3-(4'-Bromomethylbiphenyl-3-yl)-5-trichloromethyl-1,2,4-oxadiazole

To a solution of the compound (2.09 g) obtained in Working Example (43c)in CCl₄ (50 ml) were added NBS (1.10 g) and BPO (0.20 g). The mixturewas irradiated by light. The reaction mixture was cooled to roomtemperature, and insoluble materials were filtered off. The filtrate wasconcentrated to dryness. The residue was purified by columnchromatography on silica gel (Merck Art.9385 (80 g), AcOEt:nHex=1:10) toafford a colorless syrup (2.40 g, 60%).

¹ H-NMR(200 MHz,CDCl₃) δ: 4.57(2H,s), 7.49-7.68(5H,m), 7.75-7.79(1H,m),8.09-8.17(1H,m), 8.33(1H,m).

43e) Methyl 2-ethylthio-1-3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno-3,4-d!imidazole-6-carboxylate

To a solution of methyl 2-ethylthio-4-methyl-1H-thieno3,4-d!imidazole-6-carboxylate (0.80 g) in DMF (10 ml) was added sodiumhydride (60% in oil; 0.14 g) under ice-cooling. The mixture was stirredfor 10 minutes, to which was added a solution of the compound (1.53 g)obtained in Working Example (43d) in DMF (10 ml) under ice-cooling. Themixture was stirred for one hour at room temperature. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with a saturated aqueous saline solution and dried. Thesolvent was evaporated in vacuo, and the residue was purified by silicagel column chromatography to give colorless crystals. To a solution ofthe crystals in chloroform (10 ml)-methanol (10 ml) was added 1N NaOH (3ml), and the mixture was stirred for one hour at room temperature. Thereaction mixture was concentrated and adjusted to pH 3-4 with 1N HCl.The mixture was partitioned between CHCl₃ and water. The organic layerwas dried over Na₂ SO₄ and concentrated to dryness to give crudecrystals. Recrystallization from methanol-ethyl acetate affordedcolorless crystal (0.74 g, 84%), m.p.248°-151° C. (decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ O4S₂.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  58.24;        4.50;   10.87    Found:   58.24;        4.38;   10.77    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.41(3H,t), 2.63(3H,s), 3.30(2H,q),3.78(3H,s), 5.75(2H,s), 7.27(2H,d), 7.51-7.60(3H,m), 7.69-7.78(2H,m),7.98(1H,t).

IR(KBr)cm⁻¹ : 1780, 1755, 1690, 1460, 1320, 1170, 1090, 760.

43f) 2-Ethylthio-1-3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

The compound (0.60 g) obtained in Working Example (43e) was suspended intetrahydrofuran (20 ml)-H₂ O (20 ml). To the suspension was addedlithium hydride (0.25 g:5.96 mmol), and mixture was heated for 15 hoursunder reflux. The reaction mixture was concentrated, and aqueous residuewas adjusted to pH 3 with 1N-HCl. Crystals then precipitated werecollected by filtration and dried. The crystals were recrystallized toafford colorless crystals (0.33 g, 56.7%), m.p.177°-179° C. (decomp.).

Elemental Analysis for C₂₄ H₂₀ N₄ O₄ S₂.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  57.47;        4.22;   11.17    Found:   57.63;        4.04;   11.17    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.35(3H,t), 2.56(3H,s), 3.26(2H,q),5.73(2H,s), 7.26(2H,d), 7.65(1H,t), 7.69(2H,d), 7.81(1H,td),7.90(1H,td), 8.08(1H,t).

IR(KBr)cm⁻¹ : 1770, 1755, 1650, 1530, 1460, 1165, 765.

Working Example 44 2-Ethylthio-1-4'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!-imidazole-6-carboxylic acid

44a) 4'-Methyl-4-cyanobiphenyl

This compound was synthesized in the similar procedure as in WorkingExample (43a), m.p.108°-109° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.42(3H,s), 7.29(2H,d), 7.50(2H,d),7.64-7.75(4H,m).

IR(KBr)cm⁻¹ : 2225, 1495, 815.

44b) 4'-Methylbiphenyl-4-carboxamide oxime

This compound was synthesized by the similar procedure as in WorkingExample (43b).

44c) 3-(4'-Methylbiphenyl-4-yl)-5-trichloromethyl-1,2,4-oxadiazole

This compound was synthesized by the similar procedure as in WorkingExample (43c), m.p.126°-127° C. The yield was 75%.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.42(3H,s), 7.29(2H,d), 7.55(2H,d),7.72(2H,d), 8.17(2H,d).

IR(KBr)cm ⁻¹ : 1610, 1585, 1540, 1470, 1420, 1345, 905, 855, 845, 825,810, 755, 725.

44d) 3-(4'-Bromomethylbiphenyl-4-yl)-trichloromethyl-1,2,4-oxadiazole

The title compound was obtained as colorless needles (71%) from thecompound obtained in Working Example (44c) in the similar manner as inWorking Example (43d), m.p. 113°-116° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 4.56 (2H,s), 7.51(2H,d), 7.64(2H,d),7.73(2H,d), 8.20(2H,d).

IR(KBr) cm⁻¹ : 1475, 1400, 1350, 845, 830, 800, 760, 725.

44e) Methyl 2-ethylthio-1-4'-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl)biphenyl-4-yl!-4-methylthieno3,4-d!imidazole-6-carboxylate

The title compound was obtained as pale yellow crystals (0.4 g, 25%)from the compound (1.53 g) obtained in Working Example (44d) in thesimilar manner as in Working Example (43e), m.p. 251°-255° C. (decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ O₄ S₂

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  58.85;        4.43;   10.98    Found:   58.89;        4.35;   10.81    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.36(3H,t), 2.57(3H,s), 3.27(2H,q),3.70(3H,s), 5.70(2H,s), 7.22(2H,d), 7.72(2H,d), 7.87(4H,s).

IR(KBr)cm ⁻¹ : 1760,1690, 1460, 1320, 1305, 1255, 1240, 1160, 1090, 760.

44f) 2-Ethylthio-1-4'-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

The title compound was obtained as colorless crystals (0.29 g, 90%) fromthe compound (0.33 g) obtained in Working Example (44e) in the similarmanner as in Working Example (43f), m.p. 202°-204° C. (decomp.).

Elemental Analysis for C₂₄ H₂₀ N₄ O₄ S₂

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  57.68;        4.19;   11.21    Found:   57.83;        4.48;   11.39    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.35(3H,t), 2.56(3H,s), 3.26(2H,q),5.72(2H,s), 7.24(2H,d), 7.72(2H,d), 7.87(4H,s).

IR(KBr)cm ⁻¹ : 1760, 1640, 1610, 1600, 1535, 1460, 1165, 770.

Working Example 45 2-Ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)methylbiphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

45a) 4'-Methyl-2-hydroxymethylbiphenyl

To an ice-cooling suspension of lithium aluminium hydride (1.79 g) intetrahydrofuran (50 ml) was added dropwise a solution of4'-methylbiphenyl-2-carboxylic acid (5.0 g) in tetrahydrofuran (30 ml).The mixture was stirred for 17 hours at room temperature. To thereaction mixture were added ethyl acetate (10 ml) and water (50 ml), andinsoluble materials were removed by filtration through celite. Thefiltrate was concentrated to dryness, and the residue was dissolved inethyl acetate. The solution was washed with a saturated aqueous solutionof sodium hydrogencarbonate and dried. The solvent was evaporated underreduced pressure, and the residue was purified by column chromatographyon silica gel to afford the title compound as colorless syrup (3.95 g,84%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 4.62(2H,s), 7.20-7.41(7H,m),7.51-7.56(1H,m).

IR(Neat)cm ⁻¹ : 3350, 3020, 2920, 1480, 1440, 1030, 1000, 820, 755.

45b) 4'-Methyl-2-chloromethylbiphenyl

To an ice-cooling solution of the compound (3.95 g) obtained in WorkingExample (45a) in chloroform (50 ml) was added dropwise thionyl chloride(3.56 g). To the mixture was further added one drop ofdimethylformamide, and the mixture was heated for one hour under reflux.The reaction mixture was concentrated to dryness, and the residue wassuspended with a saturated aqueous solution of sodium hydrogen carbonateand extracted with ethyl acetate. The extract was washed with water anddried, and the solvent was evaporated under reduced pressure to affordthe title compound as a pale yellow oil (4.15 g, 96%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 4.53(2H,s), 7.23-7.41(7H,m),7.50-7.56(1H,m).

IR(Neat)cm ⁻¹ : 1480, 1440, 1260, 1000, 825, 820, 755, 690, 665.

45c) 4'-Methyl-2-cyanomethylbiphenyl

To a solution of the compound (4.15 g) obtained in Working Example (45b)in acetonitrile (50 ml) were added potassium cyanide (2.5 g) and18-crown-6 (-0.5 g). The mixture was heated for 10 hours under reflux.Insoluble materials were filtered off, and the filtrate was concentratedto dryness. The residue was dissolved in ethyl acetate, washed withwater and dried. The solvent was evaporated under reduced pressure, andthe residue was purified by column chromatography on silica gel toafford the title compound as a pale yellow oil (3.71 g, 93%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 3.62(2H,s), 7.14-7.39(7H,m),7.50-7.55(1H,m).

IR(Neat)cm⁻¹ : 2240, 1480, 820, 760.

45d) 4'-Methylbiphenyl-2-acetamidoxime

To a solution of hydroxylamine hydrochloride (1.68 g) in dimethylsulfoxide (10 ml) was added a solution of 28% sodium methoxide inmethanol solution (4.65 g), and the mixture was stirred for 20 minutesat room temperature. To this mixture was added a solution of thecompound obtained in Working Example (45c) in dimethyl sulfoxide (3 ml),and the mixture was stirred for 1.5 hour at 100° C. The reaction mixturewas partitioned between water and ethyl acetate. The organic layer waswashed with water and dried, and then the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel to afford the title compound as colorless crystals (0.92 g,79%), m.p.127°-128° C.

⁻¹ H-NMR(200 MHz,CDCl₃) δ:2.40(3H,s), 3.46(2H,s), 4.33(2H,br s),7.18-7.43(8H,m).

IR(KBr)cm⁻¹ : 3450, 3350, 1670, 1590, 1480, 1380, 940, 820, 760.

45e) 3-(4'-Methylbiphenyl-2-yl)methyl-5-trichloromethyl-1,2,4-oxadiazole

The compound obtained in Working Example 45d) (0.92 g) was suspended intoluene (20 ml). To the suspension was added trichloroacetic anhydride(1.42 g), and the mixture was stirred for one hour at -80°-90° C. Thereaction mixture was concentrated to dryness, and the residue wasdissolved in ethyl acetate, followed by washing with water and dried.The solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel to afford the titlecompound as a colorless oil (1.25 g, 88%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.40(3H,s), 4.11(2H,s), 7.19-7.42(8H,m).

IR(Neat)cm⁻¹ : 1580, 1490, 1355, 1050, 860, 820, 800, 760, 735, 705.

45f)3-(4'-Bromomethylbiphenyl-2-yl)methyl-5-trichloromethyl-1,2,4-oxadiazole

To a solution of the compound (1.25 g) obtained in Working Example (45e)in carbon tetrachloride (20 ml) were added N-bromosuccinimide (0.67 g)and α,α'-azobis isobutyronitrile (0.1 g), and the mixture was heated forone hour under reflux. Insoluble materials were filtered off, and thefiltrate was concentrated to dryness. The residue was purified by columnchromatography on silica gel to afford a pale yellow syrup (0.91 g,60%).

¹ H-NMR(200 MHz,CDCl₃) δ: 4.10(2H,s), 4.55(2H,s), 7.23-7.47(8H,m).

45g) Methyl 2-ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)methylbiphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylate

To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno-3,4-d!imidazole-6-carboxylate (0.75 g) in dimethylformamide (5 ml) wasadded sodium hydride (60% in oil; 0.13 g), and the mixture was stirredfor 10 minutes. To the ice-cooling mixture was added dropwise a solutionof the compound (0.91 g) obtained in Working Example (45f) indimethylformamide (5 ml), followed by stirring for one hour at roomtemperature. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The extract was washed with asaturated aqueous saline solution and dried. The solvent was evaporatedin vacuo, and the residue was purified by silica gel columnchromatography to give a pale yellow syrup. The syrup was dissolved inchloroform (5 ml)--methanol (10 ml), and to the solution was added1N-NaOH (2 ml), followed by stirring for 30 minutes at room temperature.The reaction mixture was concentrated to dryness, and the residue wasdiluted with water. The aqueous solution was adjusted to pH 3 with1N-HCl and extracted with chloroform. The extract was washed with waterand dried, and the solvent was evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel. Crudecrystals thus obtained were recrystallized from ethyl acetate-methanolto afford the title compound as pale yellow needles (0.31 g, 20%),m.p.172°-173° C. (decomp.).

Elemental Analysis for C₂₆ H₂₄ N₄ O₄ S₂ (Molecular weight 520.63):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  59.98;        4.65;   10.76    Found:   59.78;        4.55;   10.41    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.41(3H,t), 2.61(3H,s), 3.28(2H,q),3.76(3H,s), 3.83(2H,s), 5.72(2H,s), 7.16-7.39(8H,m), 8.68(1H,br s).

IR(KBr)cm⁻¹ : 1765, 1695, 1685, 1600, 1540, 1460, 1430, 1320, 1240,1170, 1090, 760.

45h) 2-Ethylthio-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)methylbiphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylic acid

To a solution of the compound (0.25 g) obtained in working Example (45g)in tetrahydrofuran (10 ml)-water (5 ml) was added lithium hydroxidemonohydrate (0.10 g), and the mixture was heated for 30 hours underreflux. The reaction mixture was adjusted to pH⁻ 3 with 1N-HCl andextracted with chloroform. The extract was washed with water and dried,and the solvent was evaporated under reduced pressure to give crudecrystals. Recrystallization from ethyl acetate-methanol-hexane affordedthe title compound as pale yellow needles (0.18 g, 74%), m.p.184°-186°C. (decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ O₄ S₂ (molecular weight 506.61):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  59.27;        4.38;   11.06    Found:   59.10;        4.22;   10.91    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.35(3H,t), 2.55(3H,s), 3.26(2H,q),3.80(2H,s), 5.73(2H,s), 7.20-7.40(8H,m).

IR(KBr)cm⁻¹ : 1810, 1790, 1650, 1535, 1460, 1325, 1170, 760.

Working Example 46 2-Ethylthio-1-2'-(1,4-dihydro-3-trifluoromethyl-5-oxo-1,2,4-triazol-4-yl)biphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylic acid

46a) 4-(4'-Methylbiphenyl-2-yl semicarbazide

To an ice-cooling solution of (4'-methylbiphenyl-2-yl)carboxylic acid(3.0 g) and triethylamine (2.2 ml) in N,N-dimethylformamide (10 ml) wasadded DPPA (3.4 ml) under nitrogen atmosphere, and the mixture wasstirred for 4 hours at the same temperature. To the reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and dried. The solution was addeddropwise to benzene (150 ml) heated at 80° C. The mixture was thenstirred for 20 minutes at the same temperature. The isocyanate solutionthus prepared was added dropwise to a solution of hydrazine (2.0 ml) inbenzene (50 ml) heated at 70° C. during the period of 90 minutes. Thepowdery product obtained by evaporating the solvent under reducedpressure was washed with ethyl acetate and dried to afford the titlecompound as white power (2.9 g, 85%), m.p.148°-151° C.

Elemental Analysis for C₁₄ H₁₅ N₃ O.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  68.66;        6.33;   17.16    Found:   68.80;        6.34;   17.18    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.40(3H,s), 3.55(2H,bs), 6.11(1H,bs),7.0-7.4(7H,m), 8.21(1H,d), 8.32(1H,bs).

IR(KBr)cm⁻¹ : 1690, 1615, 1580, 1520.

46b) 3-Trifluoromethyl-4-(4'-methylbiphenyl-2-yl)-1,2,4-tiazol-5-one

To an ice-cooling solution of the compound (700 mg) obtained in WorkingExample (46a) in dichloromethane (10 ml) were added trifluoroaceticanhydride (0.43 ml) and pyridine (0.32 ml) under nitrogen atmosphere.The mixture was stirred for one hour under ice-cooling, and then for 20hours at room temperature. To the reaction mixture was added water, andthe mixture was extracted with chloroform. The extract was dried and thesolvent was evaporated under reduced pressure. The residue was dissolvedin benzene (8 ml), and to the solution was added phosphorus oxychloride(1.5 ml). The mixture was stirred for 4 hours at 80° C. The solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate (30 ml). The solution was washed with water and an aqueoussaline solution, and the solution was concentrated to dryness underreduced pressure. The residue was purified by column chromatography onsilica gel to afford the title compound as a pale brown oil (620 mg,66%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.42(3H,s), 7.1-7.5(7H,m), 8.17(1H,d).

IR(KBr)cm⁻¹ : 1620, 1590, 1520, 1510.

46c)4-(4'-Methylbiphenyl-2-yl)-3-methoxymethoxy-5-trifluoromethyl-1,2,4-triazole

To an ice-cooling solution of the compound (600 mg) obtained in WorkingExample (46b) and triethylamine (0.34 ml) in dichloromethane (12 ml) wasadded chloromethyl ether (0.17 ml) under nitrogen atmosphere. Themixture was stirred for 9 hours, and to the mixture were addedtriethylamine (0.15 ml) and chloromethyl ether (0.17 ml). The mixturewas stirred for 13 hours under ice-cooling. The solvent was evaporatedunder reduced pressure. To the residue was added dilute hydrochloricacid, and the mixture was extracted with ethyl acetate. The extract wasdried and concentrated to dryness under reduced pressure. The residuewas purified by column chromatography on silica gel to afford the titlecompound as a pale yellow oil (395 mg, 57%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.34(3H,s), 3.40(3H,s), 4.91(2H,s),7.0-7.5(8H,m).

IR(Neat)cm⁻¹ : 1620, 1600, 1580, 1520.

46d) 4-(4'-Bromomethylbiphenyl-2-yl)-3-methoxymethoxy-5trifluoromethyl-1,2,4-triazole

To a solution of the compound (390 mg) obtained in working Example (46c)in carbon tetrachloride (15 ml) were added N-bromosuccimide (230 mg) andα,α'-azobisisobutyronitrile (20 mg). The mixture was stirred for 4.5hours at 80° C. The reaction mixture was diluted with chloroform, andthe solution was washed with an aqueous solution of sodiumhydrogencarbonate and dried. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto afford the title compound (380 mg, 80%) as a pale yellow oil.

⁻¹ H-NMR(200 MHz,CDCl₃) δ: 3.39(3H,s), 4.48(2H,s), 4.94(2H,s),7.2-7.6(8H,m)

IR(Neat)cm⁻¹ : 1615, 1600, 1575.

46e) Methoxymethyl 2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylate

A mixture of methyl 2-ethylthio-4-methylthieno-3,4-d!imidazole-6-carboxylate (2.15 g) in a mixture of 4N-LiOH (8 ml)and methanol (25 ml) was stirred for 60 hours at 70° C. Methanol wasevaporated under reduced pressure. To the residue was added 1N-HCl.Resulting precipitates were collected by filtration, washed withchloroform and dried. The brownish powder (560 mg) thus obtained wassuspended in dichloromethane (10 ml). To the suspension were addedtriethylamine (0.35 ml) and chloromethyl methyl ether (0.19 ml). Themixture was stirred for two hours. To the reaction mixture was addeddilute hydrochloric acid, and the mixture was extracted with chloroform.The extract was dried and concentrated to dryness under reducedpressure. The residue was purified by column chromatography on silicagel to afford the title compound (445 mg, 19%) as white powder,m.p.128°-130° C.

Elemental Analysis for C₁₁ H₁₄ N₂ O₃ S₂ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  46.14;        4.93;   9.78    Found:   45.90;        4.93;   9.56    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.45(3H,t), 2.64(3H,s), 3.31(2H,q),3.53(3H,s), 5.43(2H,s), 9.29(1H,bs).

IR(KBr)cm⁻¹ : 1640, 1620, 1540.

46f) 2-Ethylthio-1-2'-(1,4-dihydro-3-trifluoromethyl-5-oxo-1,2,4-triazol-4-yl)biphenyl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylic acid

The compound (280 mg) obtained in Working Example (46e) and the compound(450 mg) obtained in working Example (46d) were dissolved inN,N-dimethylformamide (12 ml). To the ice-cooling solution was addedsodium hydride (60% in oil; 47 mg) under nitrogen atmosphere. Themixture was stirred for two hours at the same temperature. To thereaction mixture was added dilute hydrochloric acid, and the mixture wasextracted with ethyl acetate. The extract was washed with water and anaqueous saline solution and dried. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give a yellow oil (464 mg). The oil was dissolved in amixture of trifluroacetic acid (4 ml) and chloroform (5 ml). Thesolution was stirred for 5 hours at 70° C. The reaction mixture wasdiluted with chloroform, washed with water and dried, and the solventwas evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel to afford the title compound (60 mg,10%) as pale brown powder, m.p.178°-180° C. (decomp.).

Elemental Analysis for C₂₅ H₂₀ N₅ O₃ S₂ F₃.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  52.81;        3.72;   12.32    Found:   52.83;        3.54;   12.20    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.41(3H,t), 2.60(3H,s), 3.30(2H,q),5.67(2H,s), 7.0-7.5(7H,m), 8.06(1H,d).

IR(KBr)cm⁻¹ : 1655, 1620, 1595, 1580, 1530.

Working Example 47 Methyl 2-ethylthio-1- 2'-1,4-dihydro-3-methyl-5-oxo-1,2,4-triazol-4-yl!biphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylate

47a) 1-Acetyl-4-(4'-methylbiphenyl-2-yl)semicarbazide

To a solution of the compound (300 mg) obtained in Working Example (31a)in dichloromethane (5 ml) were added acetic anhydride (0.12 ml) andpyridine (0.10 ml). The mixture was stirred for 15 hours at roomtemperature. The reaction mixture was poured into ice-water andextracted with a mixture of chloroform and ethanol. The extract waswashed with water and dried, and the solvent was evaporated underreduced pressure to afford the title compound (320 mg, 90%) as whitepowder, m.p.203°-205° C.

Elemental Analysis for C₁₆ H₁₇ N₃ O₂ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  67.83;        6.05;   14.83    Found:   67.53;        5.90;   14.84    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.75(3H,s), 2.37(3H,s), 7.0-7.4(7H,m),7.55(1H,s), 7.94(1H,d), 8.33(1H,s), 9.59(1H,s).

IR(KBr)cm⁻¹ : 1660, 1615, 1595, 1540.

47b) 3-Methyl-4-(4'-methylbiphenyl-2-yl)-1,2,4-triazol-5(4H)-one

To a solution of the compound (950 mg) obtained in Working Example (31a)in benzene (20 ml) was added phosphorus oxychloride (1.2 ml), and themixture was stirred for 20 hours at 90° C. The solvent was evaporatedunder reduced pressure, and the residue was diluted with ethyl acetate,washed with water and dried. The solvent was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel to afford the title compound (460 mg, 51%) as white powder,m.p.102°-104° C.

Elemental Analysis for C₁₆ H₁₅ N₃ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  72.43;        5.70;   15.84    Found:   72.37;        5.68;   15.95    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.40(3H,s), 2.42(3H,s), 6.83(1H,bs),7.0-7.5(7H,m), 8.20(1H,d).

IR(KBr)cm⁻¹ : 1640, 1575, 1530.

47c)3-Methyl-4-(4'-methylbiphenyl-2-yl)-1-methoxymethyl-1,2,4-triazol-5(4H)-on

To an ice-cooling solution of the compound (250 ml) obtained in WorkingExample (31b) in dichloromethane (8 ml) were added chloromethyl ether(0.18 ml) and triethylamine (0.20 ml) under nitrogen atmosphere. Themixture was stirred for 23 hours at room temperature. The solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel to afford the title compound (75 mg, 25%)as a pale yellow oil.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.09(3H,s), 2.34(3H,s), 3.28(3H,s),4.95(2H,s), 7.0-7.4(8H,m).

IR(Neat)cm⁻¹ : 1715, 1640, 1590, 1570, 1515.

47d) Methyl 2-ethylthio-1- 2'-1,4-dihydro-1-methoxymethyl-3-methyl-5-oxo-1,2,4-triazol-4-yl!biphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylate

To a solution of the compound obtained in Working Example (31c) incarbon tetrachloride (5 ml) were added N-bromosuccinimide (48 mg) andα,α'-azobisisobutyronitrile (5 mg). The mixture was stirred for 5 hoursat 80° C. The reaction mixture was poured into an aqueous solution ofsodium hydrogencarbonate and extracted with chloroform. The extract wasdried and concentrated to dryness under reduced pressure. The residuewas purified by column chromatography on silica gel to give a paleyellow oil (34 mg). This oil (34 mg) and methyl2-ethylthio-4-methylthieno 3,4-d!imidazole-6-carboxylate (30 mg) weredissolved in N,N-dimethylformamide (4 ml). To the ice-cooling solutionwas added sodium hydride (60% in oil; 5 mg) under nitrogen atmosphere.The mixture was stirred overnight at room temperature and concentratedto drynes under reduced pressure. The residue was diluted with ethylacetate, and the solution was washed with water and an aqueous salinesolution, and then dried. The solvent was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel to afford the title compound (42 mg, 85%) as a pale yellow oil.

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.05(3H,d), 2.62(3H,s),3.18(3H,s), 3.30(2H,q), 3.77(3H,s), 4.91(2H,d), 5.69(2H,s),7.0-7.4(8H,m).

IR(Neat)cm⁻¹ : 1720, 1695, 1645, 1605, 1540.

47e) Methyl 2-ethylthio-1- 2'-1,4-dihydro-3-methyl-5-oxo-1,2,4-triazol-4-yl!biphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylate

The compound (42 mg) obtained in Working Example (31d) was dissolved ina mixture of trifluoroacetic acid (1 ml) and chloroform (1.5 ml), andthe solution was stirred for 12 hours at 60° C. The reaction mixture wasdiluted with chloroform, and the solution was washed with water, driedand concentrated to dryness under reduced pressure. The residue waspurified by column chromatography on silica gel to give a pale yellowoil. Crystallization from chloroform and ether afforded the titlecompound (34 mg, 87%) as pale yellow crystals, m.p.204°-206° C.

Elemental Analysis for C₂₆ H₂₅ N₅ O₃ S₂.0.4CHCl₃ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  55.88;        4.51;   12.34    Found:   55.73;        4.49;   12.57    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.44(3H,t), 2.41(3H,s), 2.63(3H,s),3.33(2H,q), 3.80(3H,s), 5.77(2H,s), 6.83(1H,bs), 7.0-7.6(7H,m),8.18(1H,t).

IR(KBr)cm⁻¹ : 1685, 1630, 1600, 1570, 1535, 1520.

Working Example 48 1-2'-(2,4-Dihydro-4-methyl-3-oxo-1,2,4-triazol-5-yl)biphenyl-4-yl!methyl!-2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylic acid

48a) 4-Methyl-1- 2-(4-phenyl)benzoyl!semicarbazide

To a solution of 4'-methylbiphenyl-2-carbonyl hydrazide (2.3 g) inchloroform (20 ml) was added methyl isocyanate (10 ml), and the mixturewas stirred for one hour at room temperature. The resulting crystallineprecipitate was collected by filtration, which was purified by columnchromatography on silica gel. Crude crystals thus obtained wererecrystallized from chloroform-methanol to afford colorless needles(0.86 g, 31%), m.p.181°-182° C.

Elemental Analysis for C₁₆ H₁₇ N₃ O₂ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  67.83;        6.05;   14.83    Found:   67.65;        6.90;   14.85    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.34(3H,s), 3.30(3H,d), 5.55(1H,br),7.21(2H,d), 7.32-7.56(6H,m), 7.85(1H,s), 9.79(1H,s).

IR(KBr)cm⁻¹ : 3380, 3250, 3220, 1690, 1645, 1540, 820, 760.

48b) 2,4-Dihydro-5-(4'-methylbiphenyl-2-yl)-4-methyl-1,2,4-triazol-3-one

The compound (0.86 g) obtained in Working Example (48a) was dissolved in1N-NaOH (8 ml), and the solution was heated for 15 hours under reflux.The reaction mixture was adjusted to pH 3-4 with 1N-HCl and extractedwith ethyl acetate. The extract was washed with water and dried. Thesolvent was evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel to give crude crystals.Recrystallization from ethyl acetate-hexane afforded the title compoundas colorless needles (0.60 g, 74%), m.p.181°-182° C.

Elemental Analysis for C₁₆ H₁₅ N₃ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  72.43;        5.70;   15.84    Found:   72.54;        5.74;   15.95    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.37(3H,s), 2.55(3H,s), 7.16(2H,d),7.22(2H,d), 7.42-7.65(4H,m), 9.72(1H,s).

IR(KBr)cm⁻¹ : 3180, 3060, 1700, 1490, 1465, 1330, 1080, 1040, 960, 820,800, 780, 760, 750, 700, 650.

48c) 24-Dihydro-2-methoxymethyl-5-(4'-methylbiphenyl-2-yl)-4-methyl-1,2,4-triazol-3-one

To an ice-cooling solution of the compound (0.40 g) obtained in WorkingExample (48b) in DMF (1 ml) was added sodium hydride (60% in oil; 72mg). The mixture was stirred for 30 minutes, and to the reaction mixturewas added chloromethyl methyl ether (0.14 g). The reaction mixture wasstirred for further 1.5 hour at 0° C. and diluted with water, followedby extraction with acetic acid. The extract was washed with water anddried. The solvent was removed under reduced pressure. The residue waspurified by column chromatography on silica gel to afford the titlecompound as a colorless oil (0.40 g, 87%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.35(3H,s), 2.55(3H,s), 3.43(3H,s),5.20(2H,s), 7.14(2H,d), 7.21(2H,d), 7.40-7.64(4H,m).

IR(Neat)cm⁻¹ : 1720, 1490, 1460, 1440, 1395, 1380, 1330, 1295, 1175,1095, 1040, 920, 820, 785, 760.

48d)5-(4'-Bromomethylbiphenyl-2-yl)-4,5-dihydro-1-methoxymethyl-4-methyl-1,2,4-triazol-3-one

The compound (0.40 g) obtained in Working Example (48c), NBS(0.23 g) andbenzoyl peroxide (17 mg) were added to carbon tetrachloride (10 ml). Themixture was refluxed under irradiation of light for one hour. Insolublematerials were filtered off, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give crude crystals. Recrystallization from ethylacetate-hexane afforded the title compound as colorless prisms (0.38 g,73%), m.p.137°-138° C.

Elemental Analysis for C₁₈ H₁₈ N₃ BrO₂.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  54.42;        4.82;   10.58    Found:   54.50;        4.66;   10.51    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.60(3H,s), 3.41(3H,s), 4.49(2H,s),5.19(2H,s), 7.29(2H,d), 7.38(2H,d), 7.45-7.67(4H,m).

IR(KBr)cm⁻¹ : 1710, 1490, 1470, 1455, 1440, 1375, 1330, 1295, 1235,1180, 1090, 915, 860, 855, 790, 765, 755, 610.

48e) Methyl 1-2'-(2,4-dihydro-2-methoxymethyl-4-methyl-3-oxo-1,2,4-triazol-5-yl)biphenyl-4-yl!methyl!-2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylate

To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno-3,4-d!imidazole-6-carboxylate (0.26 g) in DMF (1 ml) was added sodiumhydride (60% in oil; 48 mg). The mixture was stirred for 20 minutes. Tothe reaction mixture was added the compound (0.38 g) obtained in WorkingExample (36d), and the reaction mixture was stirred for further 1.5 hourat room temperature. The reaction mixture was diluted with water andextracted with ethyl acetate. The extract solution was washed with waterand dried. The solvent was removed under reduced pressure. The residuewas purified by column chromatography on silica gel to afford the titlecompound as a colorless oil (0.30 g, 55%).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,s), 2.55(3H,s), 2.63(3H,s),3.30(2H,q), 3.37(3H,s), 3.77(3H,s), 5.18(2H,s), 5.71(2H,s), 7.19(2H,d),7.25(2H,d), 7.42-7.64(4H,m).

IR(Neat)cm⁻¹ : 1705, 1605, 1540, 1460, 1440, 1320, 1240, 1170, 1095,755.

48f) Methyl 2-ethylthio-1-2'-(2,4-dihydro-4-methyl-3-oxo-1,2,4-triazol-5-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

The compound (0.30 g) obtained in Working Example (48e) was dissolved ina mixture of trifluoroacetic acid (2 ml) and chloroform (2 ml). Thesolution was stirred for 5.5 days at 60° C. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel to afford the title compound as a colorlessoil (0.27 g, 96%).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.53(3H,s), 2.63(3H,s),3.30(2H,q), 3.77(3H,s), 5.71(2H,s), 7.15(2H,d), 7.23(2H,d),7.42-7.65(4H,m).

IR(Neat)cm⁻¹ : 1700, 1600, 1540, 1460, 1435, 1320, 1240, 1195, 1170,1095, 750.

48g) 2-Ethylthio-1-2'-(2,4-dihydro-4-methyl-3-oxo-1,2,4-triazol-5-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

The compound (0.27 g) obtained in Working Example (48f) and lithiumhydroxide monohydrate (0.11 g) were dissolved in a mixture of THF (2 ml)and water (2 ml), and the solution was stirred for 8 hours at 60°-70° C.The reaction mixture was diluted with water, and insoluble materialswere filtered off, and the filtrate was adjusted to pH 3-4 with 1N-HCl.Crystalline precipitate was collected by filtration and purified bysilica gel column chromatography to give crude crystals.Recrystallization from chloroform-methanol afforded the title compoundas pale yellow prisms (70 mg, 27%), m.p.228°-229° C. (decomp.).

Elemental Analysis for C₂₅ H₂₃ N₅ O₃ S₂.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  58.35;        4.70;   13.61    Found:   58.64;        4.59;   13.71    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 1.46(3H,t), 2.44(3H,s), 2.63(3H,s),3.35(2H,q), 5.61(2H,s), 7.10(2H,d), 7.20(2H,d), 7.46-7.64(4H,m).

IR(KBr)cm⁻¹ : 1690, 1605, 1540, 1490, 1460, 1415, 1315, 1240, 1200,1170, 1100, 940, 805, 780, 760.

Working Example 49 2-Ethylthio-1-2'-(5-hydroxy-2-methyl-1,2,4-triazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

49a) 1-Methyl-1-(4'-methylbiphenyl-2-carbonyl)hydrazide

To a solution of 4'-methylbiphenyl-2-carboxylic acid (3.2 g) and DMF(one drop) in THF (35 ml) was added dropwise oxalyl chloride (2.9 g),and the mixture was stirred for further 18 hours. The reaction mixturewas concentrated under reduced pressure. The residue was added dropwiseto a solution of monomethyl hydrazine (6.9 g) in THF (80 ml). Thereaction mixture was stirred for one hour at room temperature andconcentrated to dryness under reduced pressure. The residue waspartitioned between water and ethyl acetate. The ethyl acetate layer wasseparated, washed with water and dried. The solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel to afford the title compound as a yellow oil (3.6 g, 100%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.39(3H,s), 2.62(3H,s), 4.39(2H,br),7.19-7.47(8H,m).

IR(Neat)cm⁻¹ : 3300, 3200, 1630.

49b) 1-Methyl-1- 2-(4-methylphenyl)benzoyl!semicarbazide

To a solution of the compound (3.6 g) obtained in Working Example (49a)in 1N-HCl (37 ml) was added dropwise an aqueous solution (30 ml) ofsodium isocyanate (2.6 g), and the mixture was stirred for 3 hours atroom temperature. Crystalline precipitate was collected by filtrationand recrystallized from methanol-ethyl acetate to afford the titlecompound as colorless prisms (3.1 g, 74%), m.p.217°-218° C.

Elemental Analysis for C₁₆ H₁₇ N₃ O₂ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  67.83;        6.05;   14.83    Found:   67.99;        6.02;   15.03    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.34(3H,s), 3.00(3H,s), 6.08(1H,br),7.19(2H,d), 7.24-7.50(6H,m), 8.15(1H,s).

IR(KBr)cm⁻¹ : 3470, 3330, 1680, 1645, 1610, 1520, 1460, 1390, 1340, 825,755.

49c) 1-Methyl-5-(4'-methylbiphenyl-2-yl)-3-hydroxy-1,2,4-triazole

According to the procedure described in Working Example (48b), the titlecompound was obtained as colorless prisms (2.7 g, 93%) from the compound(3.1 g) prepared in Working Example (49b).

M.p.271°-172° C.

Elemental Analysis for C₁₆ H₁₅ N₃ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  72.43;        5.70;   15.84    Found:   72.30;        5.74;   15.79    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.31(3H,s), 2.95(3H,s), 7.06(2H,d),7.18(2H,d), 7.51-7.68(4H,m), 10.84(1H,s).

IR(KBr)cm⁻¹ : 1580, 1510, 1490, 1440, 1400, 1325, 1275, 890, 880, 840,820, 760, 620.

49d)3-Ethoxycarbonyloxy-1-methyl-5-(4'-methylbiphenyl-2-yl)-1,2,4-triazole

To a suspension of the compound (0.65 g) obtained in Working Example(49c) and triethylamine (0.29 g) in methylene chloride (10 ml) was addedethyl chloroformate (0.31 g), and the mixture was stirred for 3 hours atroom temperature. The reaction mixture was washed with water and dried.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel to afford the titlecompound as a colorless oil (0.55 g, 68%).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.40(3H,t), 2.34(3H,s), 3.02(3H,s),4.37(2H,q), 7.09(2H,d), 7.16(2H,d), 7.41-7.64(4H,m).

IR(Neat)cm⁻¹ : 1780, 1505, 1360, 1230.

49e)5-(4-Bromomethylbiphenyl-2-yl)-3-ethoxycarbonyloxy-1-methyl-1,2,4-triazole

According to the procedure described in Working Example (48d), the titlecompound was obtained as a colorless oil (0.63 g, 94%) from the compound(0.55 g) obtained in Working Example (49d).

¹ H-NMR(200 MHz,CDCl₃) δ: 1,41(3H,t), 3.05(3H,s), 4.37(2H,q),4.48(2H,s), 7.19(2H,d), 7.38(2H,d), 7.45-7.66(4H,m).

IR(Neat)cm⁻¹ : 1770, 1500, 1470, 1435, 1400, 1360, 1230, 760.

49f) Methyl 1-2'-(3-ethoxycarbonyloxy-1-methyl-1,2,4-triazol-5-yl)biphenyl4-yl!methyl!-2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylate

According to the procedure described in Working Example (48e), the titlecompound was obtained as a colorless oil (0.22 g, 25%) from the compound(0.63 g) obtained in Working Example (49e).

¹ H-NMR(200 MHz,CDCl₃): 1.40(3H,t), 1.41(3H,t), 2.63(3H,s), 2.97(3H,s),3.29(2H,q), 3.76(3H,s), 4.36(2H,q), 5.69(2H,s), 7.14(4H,s),7.42-7.64(4H,m).

IR(Neat)cm⁻¹ : 1780, 1690, 1605, 1540, 1510, 1460, 1440, 1365, 1320,1240, 1170, 1090, 760.

49g) 2-Ethylthio-1-2'-(3-hydroxy-1-methyl-1,2,4-triazol-5-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!-imidazole-6-carboxylic acid

According to the procedure described in Working Example (48g), the titlecompound was obtained as colorless prisms (40 mg, 21%) from the compound(0.22 g) obtained in Working Example (49e).

M.p.236°-237° C.

Elemental Analysis for C₂₅ H₂₃ N₅ O₃ S₂.0.2H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  58.97;        4.63;   13.75    Found:   59.00;        4.76;   13.68    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.33(3H,t), 2.55(3H,s), 2.92(3H,s),3.24(2H,q), 5.69(2H,s), 7.12(4H,s-like), 7.50-7.68(4H,m).

IR(KBr)cm⁻¹ : 1690, 1640, 1600, 1585, 1540, 1460, 1415, 1370, 1305,1270, 1235, 1200, 1170, 1095, 935, 775, 765.

Working Example 50 1-2'-(2,4-Dihydro-3-oxo-1,2,4-triazol-5-yl)biphenyl-4-yl!methyl!-2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylic acid

50a) 2,5-Dihydro-5-(4'-methylbiphenyl-2-yl)-1,2,4-triazol-3-one

1-(2-(4-Methylphenyl)benzoyl!semicarbazide (4.6 g) and phosphorusoxychloride (10.3 g) were suspended in benzene (100 ml), and thesuspension was heated for 3 hours under reflux. The reaction mixture wasconcentrated to dryness under reduced pressure. To the residue was addedwater, and resulting crystalline precipitate was collected byfiltration. Recrystallization from methanol afforded the title compoundas colorless needles (3.4 g, 79%), m.p.245°-246° C. (decomp.).

Elemental Analysis for C₁₅ H₁₃ N₃ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  71.70;        5.21;   16.72    Found:   71.37;        5.42;   16.72    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 2.39(3H,s), 4.84(2H,br s), 7.17(4H,s),7.39-7.58(3H,m), 7.85-7.89(1H,m).

IR(KBr)cm⁻¹ : 3260, 3080, 1670, 1655, 1605, 1580, 1025, 820, 765, 750.

50b) 1,2-(& 2,4-)Dihydro-1,2-(&'2,4-)bis(methoxymethyl)-3-(4'-methylbiphenyl-2-yl)-1,2,4-triazol-3-one

According to the procedure described in Working Example (48c), a mixtureof the isomers (1:2) of the title compound was obtained as a colorlessoil (1.6 g, 73%) from the compound (1.6 g) obtained in Working Example(50a).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.38(3H,s), 3.09(3H,s), 3.30(1H,s),3.40(2H,s), 4.30(2H,s), 4.56(2H,s), 7.20-7.30(4H,m), 7.39-7.54(4H,m).

IR(Neat)cm⁻¹ : 2220, 1685, 1480, 1440, 1360, 1290, 1240, 1190, 1090,915, 820, 760.

50c) 3-(4'-Bromomethylbiphenyl-2-yl)-1,2-(& 2,4-)dihydro-1,2-(&2,4-)bis(methoxymethyl)-1,2,4-triazol-3-one

According to the procedure described in Working Example (48d), a mixtureof the isomers (1:2) of the title compound was obtained as a colorlessoil (2.0 g, 100%) from the compound (1.6 g) obtained in Working Example(50b).

¹ H-NMR(200 MHz,CDCl₃) δ: 3.10(3H,s), 3.23(1H,s), 3.41(2H,s),4.31(2H,s), 4.51(2H,s), 4.54(2H,s), 7.35-7.65(8H,m).

IR(Neat)cm⁻¹ : 2210, 1680, 1440, 1360, 1285, 1240, 1230, 1190, 1090,915, 760.

50d) Methyl 2-ethylthio-1- 2'-(1,2-(& 2,4-)dihydro-1,2-(&2,4-)bis-methoxymethyl)-5-oxo-1,2,4-triazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylate

According to the procedure described in Working Example (48e), a mixtureof the isomers of the title compound was obtained as a pale yellow oil(0.65 g, 43%) from the compound (1.0 g) obtained in Working Example(50c).

¹ H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t), 2.62(3H,s), 3.05(3H,s),3.16(1H,s), 3.30(2H,q), 3.36(2/3H,s), 3.77(3H,s), 4.22(2H,s),4.42(2H,s), 5.72(2H,s), 7.21-7.57(8H,m).

IR(Neat)cm⁻¹ : 2220, 1690, 1600, 1540, 1460, 1430, 1360, 1320, 1285,1240, 1195, 1165, 1090, 755.

50e) Methyl 2-ethylthio-1- 2'-(4,5-dihydro-5-oxo-1,2,4-triazol-3-ylbiphenyl-4-yl!methyl!-4-methylthieno 3,4-d!imidazole-6-carboxylate

According to the procedure described in Working Example (48f), the titlecompound was obtained as yellow prisms (0.28 g, 50%) from the compound(0.65 g) obtained in Working Example (50d).

M.p.272°-273° C. (decomp.)

Elemental Analysis for C₂₅ H₂₃ N₅ O₃ S₂ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  59.39;        4.58;   13.85    Found:   59.17;        4.74;   13.81    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.36(3H,t), 2.56(3H,s), 3.26(2H,q),3.70(.3H,s), 5.66(2H,s), 6.96(2H,br s), 7.12(2H,d), 7.22(2H,d),7.41-7.63(3H,m), 7.69(1H,dd).

IR(KBr)cm⁻¹ : 3275, 3100, 1680, 1660, 1535, 1450, 1430, 1320, 1235,1160, 1090, 755.

50f) 2-Ethylthio-1-2'-(4,5-dihydro-5-oxo-1,2,4-triazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid

According to the procedure described in Working Example (48g), the titlecompound was obtained as colorless needles (0.17 g, 65%) from thecompound (0.27 g) obtained in Working Example (50e).

M.p.205°-207° C. (decomp.)

Elemental Analysis for C₂₄ H₂₁ N₅ O₃ S₂ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  58.64;        4.31;   14.25    Found:   58.30;        4.16;   14.12    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.35(3H,t), 2.54(3H,s), 3.24(2H,q),5.70(2H,s), 6.95(2H,s), 7.15(2H,d), 7.22(2H,d), 7.41-7.63(3H,m),7.69(1H,dd).

IR(KBr)cm⁻¹ : 1660, 1650, 1595, 1535, 1450, 1305, 1240, 1160.

Working Example 51 Methyl 2-n-butyl-1-2'-(2,4-dioxoimidazolidin-1-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

51a) Methyl 2-n-butyl-1-2'-(t-butoxycarbonylamino)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

Methyl 2-butyl-1-2'-(t-butoxycarbonyl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate(600 mg) and triethylamine (0.2 ml) were dissolved inN,N-dimethylformamide (3 ml). To the ice-cooling solution was addeddropwise diphenyl phosphoryl azide (DPPA) (0.32 ml) under nitrogenatmosphere. The mixture was stirred for 4.5 hours at the sametemperature. The reaction mixture was diluted with ethyl acetate, washedwith water three times, and dried. The solution thus obtained wasconcentrated under reduced pressure to a volume of 20 ml. Theconcentrate was added dropwise to toluene (25 ml) with stirring at 80°C. The mixture was stirred for further 20 minutes at the sametemperature. To the reaction mixture was added t-butanol (15 ml), andthe mixture was stirred for 17 hours. The solvent was evaporated underreduced pressure, and the residue was purified by column chromatographyon silica gel to afford the title compound (510 mg, 73%) as a paleyellow oil.

51b) Methyl 2-n-butyl-1-(2'-aminobiphenyl-4-yl)methyl!-benzimidazole-7-carboxylate

The compound (510 mg) obtained in Working Example (51a) was dissolved inconc. HCl (0.8 ml) and methanol (10 ml), and the solution was stirredfor 70 minutes at 80° C. The solvent was removed under reduced pressure.To the residue was added an aqueous solution of sodiumhydrogencarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with water and dried. The solvent was evaporatedunder reduced pressure to give a pale yellow oil, which was crystallizedfrom ether to afford the title compound (370 mg, 90%) as white crystals,m.p.97°-99° C.

Elemental Analysis for C₂₆ H₂₇ N₃ O₂ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  75.52;        6.58;   10.16    Found:   75.27;        6.81;    9.99    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.95(3H,t), 1.4-1.6(2H,m), 1.8-2.0(2H,m),2.92(2H,t), 3.65(2H,bs), 3.73(3H,s), 5.79(2H,s), 6.7-7.5(9H,m),7.64(1H,dd), 7.95(1H,dd).

IR(KBr)cm⁻¹ : 1720, 1630, 1600, 1575, 1520.

51c) Methyl 2-n-butyl-1-2'-(ethoxycarbonylmethylamino)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The compound (408 mg) obtained in Working Example (51b) and ethylbromoacetate (0.13 ml) were dissolved in N,N-dimethylformamide (12 ml),and to the solution was added potassium carbonate (150 mg) at roomtemperature. The mixture was stirred for 63 hours at room temperature,then the solvent was removed under reduced pressure. The residue waspartitioned between water and ethyl acetate. The organic layer was driedand concentrated to dryness under reduced pressure. The residue waspurified by column chromatography on silica gel to afford the titlecompound (139 mg, 28%) as a pale yellow oil.

¹ H-NMR(200 MHz,CDCl₃) δ: 0.96(3H,t), 1.24(3H,t), 1.4-1.6(2H,m),1.8-2.0(2H,m), 2.93(2H,t), 3.73(3H,s), 3.85(2H,d), 4.17(2H,q),4.51(1H,bt), 5.79(2H,s), 6.55(1H,d), 6.7-7.5(8H,m), 7.64(1H,dd),7.95(1H,dd).

IR(Neat)cm⁻¹ : 1745, 1720, 1600, 1580, 1520, 1505.

51d) Methyl 2-n-butyl-1- 2'-(N-chloroacetylcarbamoyl)-(N-ethoxycarbonyl-methyl)aminobiphenyl-4-yl!methyl!benzimidazole-7-carboxylate

To an ice-cooling solution of the compound (260 mg) obtained in WorkingExample (51c) in dichloromethane (10 ml) was added dropwise chloroacetylisocyanate (80 micro 1) under nitrogen atmosphere. The mixture wasstirred for two hours at the same temperature and concentrated todryness. The residue was purified by column chromatography on silica gelto afford the title compound (193 mg, 60%) as white powder,m.p.149°-151° C.

Elemental Analysis for C₃₃ H₃₅ N₄ O₆ Cl.0.2H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  63.65;        5.73; 9.00    Found:   63.46;        5.65;   8.72    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.98(3H,t), 1.25(3H,t), 1.3-1.6(2H,m),1.7-2.0(2H,m), 2.91(2H,t), 3.32(1H,d), 3.75(3H,s), 4.0-4.3(2H,m),4.38(1H,d), 4.40(1H,d), 4.58(1H,d), 5.79(2H,s), 6.91(2H,d), 7.11(2H,d),7.2-7.7(6H,m), 7.95(1H,d).

IR(KBr)cm⁻¹ : 1750, 1720, 1690, 1520.

51e) Methyl 2-n-butyl-1-2'-(2,4-dioxoimidazolidin-1-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The compound (180 mg) obtained in Working Example (51d) was dissolved ina mixture of methanol (10 ml) and chloroform (3 ml). To the solution wasadded sodium N-methyldithiocarbamate (48 mg) at room temperature undernitrogen atmosphere. The mixture was stirred for 5 hours at roomtemperature, and the solvent was removed under reduced pressure. Theresidue was purified by column chromatography on silica gel to give acolorless oil (137 mg). To an ice-cooling solution of the oil inN,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil; 13mg) under nitrogen atmosphere. The mixture was stirred for two hoursunder ice-cooling, then 4 hours at room temperature. After evaporationof the solvent, the residue was diluted with chloroform, and thesolution was washed with dilute hydrochloric acid and dried. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel to give a yellow oil. This productwas crystallized from chloroform and ether to afford the title compound(40 mg, 32%) as pale yellow powder, m.p.175°-178° C.

Elemental Analysis for C₂₉ H₂₈ N₄ O₄.0.3H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  69.39;        5.74;   11.16    Found:   69.47;        5.83;   10.98    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.95(3H,t), 1.3-1.6(2H,m), 2.95(2H,t),3.68(2H,s), 3.71(3H,s), 5.79(2H,s), 6.89(2H,d), 7.1-7.5(7H,m),7.63(1H,d), 7.97(1H,dd), 8.14(1H,bs).

IR(KBr)cm⁻¹ : 3450, 2960, 2740, 1770, 1730, 1610, 1525.

Working Example 52 Methyl 2-butyl-1- 2'-(2,4-dioxo-3H-thiazolidin-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

52a) Methyl 2- N-(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl-N-valeryl!amino-3-nitrobenzoate

To a solution of methyl 3-nitro-2-valerylaminobenzoate (2.79 g) in DMF(20 ml) was added sodium hydride (60% in oil; 0.40 g) with stirringunder ice-cooling. After stirring for fifteen minutes,2'-tert-butoxycarbonyl biphenyl methyl bromide (4.51 g, 13 mmol) wasadded to the mixture. The reaction mixture was stirred for two hours at70° C. and extracted with ethyl acetate. The extract was washed withwater and dried (MgSO₄), and the solvent was evaporated in vacuo. Theresidue was purified by column chromatography on silica gel to givecrude crystals. Recrystallization from isopropyl ether afforded thetitle compound (4.41 g, 81%) as colorless crystals, m.p.127°-128° C.

Elemental Analysis for C₃₁ H₃₄ N₂ O₇ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  68.12;        6.27; 5.12    Found:   68.27;        6.27;   4.85    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.80(3H,t), 1.20(2H,m), 1.23(9H,s),1.53(2H,m), 2.05(2H,t), 3.62(3H,s), 4.56 and 4.77(2H,each d),7.05(2H,d), 7.13(2H,d), 7.27-7.83(5H,m), 8.12(1H,dd), 8.23(1H,dd).

IR(Nujol)cm⁻¹ : 1740, 1710, 1675, 1600.

52b) Methyl 2-butyl-1-2'-tert-butoxycarbonylbiphenyl-4-yl!methylbenzimidazole-7-carboxylate

Iron powder (1.35 g) was added to a mixture of the compound (3.20 g)obtained in Working Example (52a) in a mixture of conc. HCl (0.5 ml) andmethanol (30 ml). The mixture was heated for 1.5 hour under reflux.Insoluble materials were filtered off through celite. The filtrate wasconcentrated to dryness, and to the residue were added conc. HCl (0.5ml) and methanol (50 ml). The mixture was heated for 1.5 hour underreflux and concentrated to dryness. The residue was partitioned betweenwater and chloroform. The organic layer was dried and concentrated todryness. The residue was purified by column chromatography on silica gelto afford the title compound (2.38 g, 82%) a an oil.

Elemental Analysis for C₃₁ H₃₄ N₂ O₄. 1/2H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  73.35;        6.95;   5.52    Found:   73.42;        6.98;   5.45    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.97(3H,t), 1.19(9H,s), 1.48(2H,m),2.93(2H,t), 3.76(3H,s), 5.83(2H,s), 6.87(2H,d), 7.16-7.51(6H,m),7.64-7.77(2H,m), 7.95(1H,dd).

IR(Neat)cm⁻¹ : 1715, 1700, 1595.

52c) Methyl 2-butyl-1-2'-carboxylbiphenyl-4-yl!methylbenzimidazole-7-carboxylate

Trifluoroacetic acid (10 ml) was added to a solution of the compound(2.35 g) obtained in Working Example (52b) in dichloromethane (8 ml).The mixture was stirred for one hour at room temperature, diluted withwater and extracted with chloroform. The extract was washed with waterand dried (MgSO₄), and the solvent was evaporated in vacuo. The residuewas purified by column chromatography on silica gel to give crystals.Recrystallization from diethyl ether afforded the title compound (2.04g, 98%) as colorless prisms, m.p.192°-194° C.

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.90(3H,t), 1.40(2H,m), 1.78(2H,m),2.94(2H,t), 3.65(3H,s), 3.84(1H,br), 5.73(2H,s), 6.87(2H,d),7.22-7.57(7H,m), 7.70(1H,dd), 7.88(1H,dd).

IR(Nujol)cm⁻¹ : 3420, 1725, 1690, 1600.

52d) Methyl 2-butyl-1-2'-hydroxymethylbiphenyl-4-yl!methylbenzimidazole-7-carboxylate

A mixture of methyl 2-butyl-1-2'-carboxybiphenyl-4-yl!methylbenzimidazole-7-carboxylate (0.44 g) andthionyl chloride (0.15 ml) in chloroform (4 ml) was heated for 30minutes under reflux with stirring. The reaction mixture wasconcentrated, and the resulting product was used for the subsequentreaction without purification. A stirred solution of the above productin tetrahydrofuran (6 ml) was added dropwise to a suspension ofaluminium lithium hydride (40 mg) in tetrahydrofuran (6 ml) underice-cooling. The reaction mixture was stirred for one minutes at thesame temperature, and to the mixture were added 2N-HCl and, then water,followed by extraction with chloroform. The extract was washed withwater and dried (MgSO₄), and the solvent was evaporated in vacuo. Theresidue was purified by column chromatography on silica gel to give anoil. Crystallization of this product from isopropyl ether affordedcolorless prisms (0.13 g, 31%), m.p.126°-127° C.

Elemental Analysis for C₂₇ H₂₈ N₂ O₃ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  75.68;        6.59;   6.54    Found:   75.20;        6.66;   6.55    ______________________________________

52e) Methyl 2-butyl-1- 2'-formylbiphenyl-4-yl!methylbenzimidazole-7-carboxylate

A mixture of the compound (0.73 g) obtained in Working Example (52d),pyridinium dichromate (0.75 g) and dichloromethane (20 ml) was stirredfor 15 hours at room temperature. Insoluble materials were filtered offthrough celite, and the filtrate was concentrated to dryness. Theresidue was purified by column chromatography on silica gel to givecrude crystals. Recrystallization from ethyl acetate-diethyl etherafforded colorless prisms (0.62 g, 85%), m.p.103°-104° C.

Elemental Analysis for C₂₇ H₂₆ N₂ O₃ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  76.03;        6.14;   6.57    Found:   75.95;        6.07;   6.56    ______________________________________

¹ H-NMR(200 MHz,CDCl₃) δ: 0.96(3H,t), 1.48(2H,m), 1.89(2H,m),2.93(2H,t), 3.74(3H,s), 5.84(2H,s), 6.96(2H,d), 7.22-7.72(7H,m),7.94-8.06(2H,m), 9.91(1H,s).

IR(Nujol)cm⁻¹ : 1720, 1695, 1595.

52f) Methyl 2-butyl-1-2'-cyanohydroxymethylbiphenyl-4-yl!methylbenzimidazole-7-carboxylate

To a solution of the compound (0.61 g) obtained in Working Example (52e)in ethyl acetate (6 ml) were added an aqueous solution (1.5 ml) ofsodium hydrogensulfate (0.74 g) and an aqueous solution (1.5 ml) ofpotassium cyanide (0.47 g). The reaction mixture was stirred for twohours at room temperature, and then for one hour at 60° C. The mixturewas diluted with water and extracted with ethyl acetate. The extract waswashed with water and dried (MgSO₄) and concentrated to dryness. Theresidue was purified by column chromatography on silica gel to affordthe title compound (0.61 g, 94%) as a syrup.

¹ H-NMR(200 MHz,CDCl₃) δ: 0.87(3H,t), 1.36(2H,m), 1.71(2H,m),2.80(2H,t), 3.74(3H,s), 5.47(1H,s), 5.75(2H,s), 6.85(2H,d),7.16-7.93(9H,m).

IR(Neat)cm⁻¹ : 3420, 2360, 1720, 1605.

52g) Methyl 2-butyl-1-2'-(2,4-dioxothiazolidin-5-yl)biphenyl-4-yl!methylbenzimidazole-7-carboxylate

Thionyl chloride (0.15 ml, 2.1 mmol) was added to a solution of thecompound (0.60 g) obtained in Working Example (52f) in chloroform (6ml). The solution was heated for one hour under reflux. The reactionmixture was concentrated, and the residue was used in the subsequentreaction without purification.

A mixture of the compound obtained above and thiourea (0.11 g) inmethanol (10 ml) was heated for one hour under reflux. After addition of2N-HCl (13 ml), the reaction mixture was heated for 12 hours underreflux. The reaction mixture was diluted with water and extracted withchloroform. The extract was washed with water and dried (MgSO₄), and thesolvent was evaporated in vacuo. The residue was purified by columnchromatography on silica gel to give crystals. Recrystallization fromdichloromethane-ethyl acetate afforded the title compound (0.40 g, 59%)as colorless prisms, m.p.241°-142° C.

Elemental Analysis for C₂₉ H₂₇ N₃ O₄ S:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  67.82;        5.30;   8.18    Found:   67.71;        5.62;   8.14    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 0.89(3H,t), 1.40(2H,m), 1.78(2H,m),2.91(2H,t), 3.69(3H,s), 5.46(1H,s), 5.76(2H,s), 6.93(2H,d),7.15-7.61(8H,m), 7.87(1H,d), 12.28(1H,br).

IR(Nujol)cm⁻¹ : 1745, 1725, 1700, 1605.

Working Example 53 2-Ethylthio-1-3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylic acid

53a) Methyl 4'-methylbiphenyl-3-carboxylate

To a mixture of methyl 3-iodobenzoate (26.1 g) in 4-iodotoluene (21.9 g)was added copper powder (31.8 g) gradually at 180°-190° C. The mixturewas then stirred for 6 hours at 200°-210° C. The reaction mixture wascooled to room temperature, to which was added toluene. Insolublematerials were filtered off, and the filtrate was concentrated todryness. The residue was purified by column chromatography on silica gelto afford the title compound as a colorless oil (6.61 g, 29%).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.40(3H,s), 3.94(3H,s), 7.26(2H,d),7.49(1H,t), 7.52(2H,d), 7.77(1H,m), 7.99(1H,td), 8.26(1H,t).

53b) 4'-Methylbiphenyl-3-carboxylic acid

To a solution of the compound (2.36 g) obtained in Working Example (53a)in tetrahydrofuran (20 ml)-water (10 ml) was added lithium hydroxidemonohydrate (1.31 g). The mixture was stirred for 3 hours at roomtemperature. The reaction mixture was concentrated, diluted with waterand washed with ethyl acetate. The aqueous layer was adjusted to pH 3with 1N-HCl. Crystalline precipitate was collected by filtration anddried to afford the title compound as colorless needles (1.73 g, 78%),m.p.182°-187° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 7.28(2H,d), 7.54(1H,t),7.54(2H,d), 7.83(1H,m), 8.08(1H,td), 8.35(1H,t).

IR(KBr)cm⁻¹ : 1700, 1450, 1415, 1310, 1300, 1270, 1260, 810, 755, 720.

53c) 4'-Methylbiphenyl-3-carboxamide

To a suspension of the compound (1.73 g) obtained in Working Example(53b) in chloroform (25 ml) were added thionyl chloride (1.94 g) anddimethylformamide (two drops). The mixture was heated for 4 hours underreflux. The reaction mixture was concentrated to dryness and to theresidue was added toluene. The mixture was again concentrated todryness. This procedure was repeated four times to give a pale yellowoil, which was added dropwise to 25% aqueous ammonia (20 ml) underice-cooling. The mixture was stirred for 30 minutes at room temperature.Crystalline precipitate then formed was collected by filtration anddried to afford the title compound as colorless crystals (1.73 g,quantitatively), m.p.200°-205° C.

¹ H-NMR(200 MHz,DMSO-d₆) δ: 2.36(3H,s), 7.30(2H,d), 7.41(1H,br s),7.51(1H,t), 7.63(2H,d), 7.76-7.86(2H,m), 8.10(1H,br s), 8.14(1H,t).

IR(KBr)cm⁻¹ : 3300, 3150, 1670, 1630, 1605, 1580, 1450, 1410, 1390,1125, 800, 685.

53d) 4'-Methyl-3-cyanobiphenyl

A mixture of the compound (1.70 g) obtained in Working Example (53c) inthionyl chloride (10 ml) was heated for 4.5 hours under reflux. Thereaction mixture was concentrated to dryness and to the residue wasadded toluene. The mixture was again concentrated to dryness. Thisprocedure was repeated three times, then the residue was purified bycolumn chromatography on silica gel to afford the title compound ascolorless crystals (1.50 g, 96%), m.p.71°-73° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 7.28(2H,d), 7.46(2H,d),7.51(1H,t), 7.60(1H,td), 7.79(1H,td), 7.84(1H,t).

IR(KBr)cm⁻¹ : 2230, 1475, 825, 800.

53e) 4'-Methylbiphenyl-3-carboxyamidoxime

To a solution of hydroxylamine hydrochloride (2.61 g) in dimethylsulfoxide (20 ml) was added a solution of 28% sodium methoxide inmethanol (7.25 g). The mixture was then stirred for 10 minutes at roomtemperature, to which was added a solution of the compound (1.45 g)obtained in Working Example (53d) in dimethyl sulfoxide (10 ml). Themixture was stirred for one hour at 100° C., and water was added to themixture. The mixture was extracted with ethyl acetate. The extract waswashed with water, dried and concentrated to dryness in vacuo. Theresidue was purified by column chromatography on silica gel to affordthe title compound as colorless crystals (1.30 g, 76%), m.p.134°-136° C.

¹ H-NMR(200 MHz,CDCl₃) δ: 2.39(3H,s), 4.93(2H,br s), 7.25(2H,d),7.41-7.66(5H,m), 7.85(1H,t).

IR(KBr)cm⁻¹ : 3495, 3385, 1660, 1585, 1440, 1375, 940, 925, 900, 795.

53f) 3-(4'-Methylbiphenyl-3-yl)-5-trichloromethyl-1,2,4-oxadiazole

To a suspension of the compound (1.30 g) obtained in Working Example(53e) in toluene (30 ml) was added trichloroacetic anhydride (2.13 g),and the mixture was stirred for 30 minutes at 80° C. The reactionmixture was concentrated to dryness and dissolved in ethyl acetate. Thesolution was washed with water, dried and concentrated to dryness invacuo. The residue was purified by column chromatography on silica gelto afford the title compound as an oil (2.09 g, quantitatively).

¹ H-NMR(200 MHz,CDCl₃) δ: 2.41(3H,s), 7.28(2H,d), 7.55(2H,d),7.56(1H,t), 7.76(1H,td), 8.07(1H,td), 8.32(1H,t),

IR(Neat)cm⁻¹ : 1570, 1515, 1460, 1355, 1335, 850, 825, 800, 745, 690.

53g) 3-(4'-Bromomethylbiphenyl-3-yl)-5-trichloromethyl-1,2,4-oxadiazole

To a solution of the compound (2.09 g) obtained in Working Example (53f)in carbon tetrachloride (50 ml) were added N-bromosuccinimide (NBS)(1.10 g) and benzoyl peroxide (BPO) (0.20 g). The mixture was refluxedunder irradiation of light for one hour. The reaction mixture was cooledto room temperature, and insoluble materials were filtered off. Thefiltrate was concentrated to dryness, and the residue was purified bycolumn chromatography on silica gel to afford the title compound as acolorless oil (2.40 g, 59%).

¹ H-NMR(200 MHz,CDCl₃): 4.57(2H,s), 7.49-7.68(5H,m), 7.75-7.79(1H,m),8.09-8.17(1H,m), 8.33(1H,m).

53h) Methyl 2-ethylthio-1-3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylate

To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylate (0.80 g) in dimethylformamide (10 ml) wasadded sodium hydride (60% in oil; 0.14 g). After stirring for 10minutes, a solution of the compound (1.53 g) obtained in Working Example(53g) in dimethylformamide (10 ml) was added to the mixture underice-cooling, followed by stirring for one hour at room temperature. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The extract was washed with a saturated aqueous salinesolution, dried and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel to give a colorless crystallineproduct. To a solution of the crystals in a mixture of chloroform (10ml)-methanol (10 ml) was added 1N-NaOH (3 ml), and the mixture wasstirred for one hour at room temperature. The reaction mixture wasconcentrated and adjusted to pH 3-4 with 1N HCl. The aqueous mixture waspartitioned between chloroform and water. The organic layer was driedand the solvent was removed in vacuo to give crude crystals.Recrystallization from methanol-ethyl acetate afforded the titlecompound as colorless needles (0.74 g, 83%), m.p.248°-251° C. (decomp.).

Elemental Analysis for C₂₅ H₂₂ N₄ S₂.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  58.24;        4.50;   10.87    Found:   58.24;        4.38;   10.77    ______________________________________

¹ H-NMR(200 MHz,CDCl₃): 1.41(3H,t), 2.63(3H,s), 3.30(2H,q), 3.78(3H,s),5.75(2H,s), 7.27(2H,d), 7.51-7.60(3H,m), 7.69-7.78(2H,m), 7.98(1H,t).

IR(KBr)cm⁻¹ : 1780, 1755, 1690, 1460, 1320, 1170, 1090, 760.

53i) 2-Ethylthio-1-3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!thieno3,4-d!imidazole-4-methyl-6-carboxylic acid

To a suspension of the compound (0.60 g) obtained in Working Example(53h) in a mixture of tetrahydrofuran (20 ml)-water (20 ml) was addedlithium hydroxide monohydrate (0.25 g). The mixture was heated for 15hours under reflux. The reaction mixture was concentrated, and theaqueous residue was adjusted to pH 3 with 1N-HCl. Crystallineprecipitate was recrystallized to afford colorless needles (0.33 g,56%), m.p.177°-179° C. (decomp.).

Elemental Analysis for C₂₄ H₂₀ N₄ O₄ S₂.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  57.47;        4.22; 11.17    Found:   57.63;        4.04;   11.17    ______________________________________

¹ H-NMR(200 MHz,DMSO-d₆) δ: 1.35(3H,t), 2.56(3H,s), 3.26(2H,q),5.73(2H,s), 7.26(2H,d), 7.65(1H,t), 7.69(2H,d), 7.81(1H,td),7.90(1H,td), 8.08(1H,t).

IR(KBr)cm⁻¹ : 1770, 1755, 1650, 1530, 1460, 1165, 765.

Working Example 54 2-Ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid 54a) 4'-bromomethylbiphenyl-2-carboxamide

A mixture of 4'-methylbiphenyl-2-carboxamide (2.1 g),N-bromo-succinimide (2.5 g) and azobisisobutyronitrate (AIBN; 82 mg) inbenzene (20 ml) was stirred for 20 hours at 60° to 70° C. Resultingcrystalline precipitates were collected by filtration, washed withisopropylether and suspended in water. The suspension was stirred for 30minutes, and insoluble materials were collected by filtration and driedto give crude crystals. Recrystallization from ethyl acetate-methanolafforded colorless needles (1.6 g, 55%), m.p. 220°-221° C.(decomp.).

Elemental Analysis for C₁₄ H₁₂ BrNO:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  57.95;        4.17;   4.83    Found:   57.85;        4.16;   4.77    ______________________________________

¹ H-NMR (200 MHz, DMSO-d₆) δ: 4.75(2H,s), 7.31-7.69(10H,m)

IR(KBr)cm⁻¹ : 3150, 3000, 1570, 1520, 1500, 1300, 665.

54b) Methyl 2-N-tert-butoxycarbonyl-N-(2'-carbamoylbiphenyl-4-yl)methylamino!-3-nitrobenzoate

A mixture of methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (1.8g), 4'-bromomethylbiphenyl-2-carboxamide (1.8 g) and K₂ CO₃ (0.86 g) inacetonitrile (25 ml) was heated for 6 hours under reflux. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The extract was washed with water and dried over MgSO₄.The solvent was removed in vacuo, and the residue was purified by columnchromatography on silica gel to afford a yellow syrup (2.3 g, 90%).

¹ H-NMR (200 MHz, CDCl₃) δ: 1.35(9H,s), 3.83(3H,s), 4.48(1H,d),4.92(1H,d), 5.29(1H,brs), 5.56(1H,brs), 7.13-7.54(8H,m),7.80-7.91(2H,m), 8.06(1H,dd).

IR(neat)cm⁻¹ : 1740-1660, 1600, 1535, 1480, 1450, 1160, 1130, 860, 830,760.

54c) Methyl 2-(2'-carbamoylbiphenyl-4-yl)methylamino-3-nitrobenzoate

A mixture of the compound (2.8 g) obtained in Example (54b) in methanol(15 ml) and 1N-HCl (6 ml) was heated for 2 hours under reflux. Afterremoval of the solvent, the residue was made alkaline with an aqueoussolution of NaHCO₃, and the mixture was extracted with ethyl acetate.The extract was washed with water, dried over MgSO₄ and concentrated todryness. The residue was purified by column chromatography on silicagel, and the product was recrystallized from ethyl acetate-hexane toafford yellow needles (1.6 g, 73%).

¹ H-NMR (200 MHz, CDCl₃) δ: 3.90(3H,s), 4.25(2H,s), 5.20(1H,brs),5.46(1H,brs), 6.73(1H,t), 7.32-7.54(7H,m), 7.78(1H,dd), 7.97(1H,dd),8.12(1H,dd).

IR(KBr)cm⁻¹ : 3470, 3330, 1695, 1670, 1605, 1580, 1530, 1500, 1450,1350, 1260, 1120, 1110, 765, 745.

54d) Methyl 3-amino-2-(2'-carbamoylbiphenyl-4-yl)methyl-aminobenzoate

To a suspension of nickel chloride (4 mg) in methanol (20 ml) was addeda small amount of NaBH₄ was added the compound (1.2 g) obtained inExample (54c) (1.2 g). To the ice-cooling reaction mixture was addedNaBH₄ (0.45 g) in portions during a period of 30 minutes. After stirringfor further 30 minutes, the reaction mixture was partitioned betweenwater and ethyl acetate. The organic layer was washed with water anddried over MgSO₄. The solvent was removed in vacuo, and the residue waspurified by column chromatography on silica gel to afford a colorlesssyrup (0.84 g, 76%).

¹ H-NMR (200 MHz, CDCl₃) δ: 3.80(3H,s), 4.25(2H,s), 5.12(1H,brs),5.42(1H,brs), 6.88-6.94(2H,m), 7.20-7.56(8H,m), 7.78-7.83(1H,m).

IR(neat)cm⁻¹ : 3450, 3350, 3180, 1700-1660, 1610, 1470, 1380, 1290,1200, 760.

54e) Methyl 1-(2'-carbamoylbiphenyl-4-yl)methyl!-2-ethoxybenzimidazole-7-carboxylate

To dioxane (2 ml) were added the compound (0.84 g) obtained in Example(54d), tetraethoxymethane (0.63 g) and acetic acid (0.13 g), and themixture was stirred for 6 hours at 80°-90° C. The solvent was removed invacuo, and the residue was purified by column chromatography on silicagel. Recrystallization from ethyl acetate-hexane afforded colorlessneedles (0.61 g, 64%), m.p. 198°-199° C.

Elemental Analysis for C₂₅ H₂₃ N₃ O₄ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  69.92;        5.40;   9.78    Found:   69.96;        5.68;   9.81    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.52(3H,t), 3.78(3H,s), 4.73(2H,q),5.14(1H,brs), 5.39(1H,brs), 5.66(2H,s), 7.03(2H,d), 7.20(1H,t),7.30-7.56(6H,m), 7.73-7.81(2H,m).

IR(KBr)cm⁻¹ : 3400, 3200, 1720, 1660, 1620, 1540, 1475, 1430, 1380,1350, 1280, 1250, 1040, 755, 740.

54f) Methyl 2-ethoxy-1- (2'-ethoxycarboimidoyl!biphenyl-4-yl)methyl!benzimidazole-7-carboxylate

To methylene chloride (50 ml) were added the compound (4.3 g) obtainedin Example (54e) and triethyl tetrafluoroborate (2.8 g). The mixture wasstirred for one hour at room temperature. The reaction mixture waswashed with a saturated aqueous solution of NaHCO₃ and dried over MgSO₄.The solvent was removed in vacuo, and the residue was purified by columnchromatography on silica gel. Recrystallization from isopropyletherafforded colorless prisms (3.6 g, 78%), m.p. 105°-106° C.

Elemental Analysis for C₂₇ H₂₇ N₃ O₄ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  70.88;        5.95;   9.18    Found:   70.66;        5.96;   9.16    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 0.92(3H,t), 1.50(3H,t), 3.79(3H,s),4.01(2H,q), 4.67(2H,q), 5.66(2H,s), 7.02(2H,d), 7.13-7.58(8H,m),7.73(1H,dd).

IR(KBr)cm⁻¹ : 3310, 1715, 1640, 1620, 1550, 1480, 1460, 1430, 1390,1375, 1350, 1330, 1280, 1250, 1220, 1170, 1130, 1110, 1080, 1040, 1005,870, 760, 750, 740.

54g) Methyl 2-ethoxy-1- 2'-(N-methoxycarbonyl)ethoxycarboimidoyl!biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

To toluene (10 ml) were added the compound (1.5 g) obtained in Example(54f), ethyl chloroformate (0.41 g) and 2,6-dimethylpyridine (0.46 g),and the mixture was stirred for 3 hours at 80°-90° C. The reactionmixture was diluted with ethyl acetate, washed with a saturated aqueoussolution of NaHCO₃ and dried over MgSO₄. The solvent was removed invacuo, and the residue was recrystallized from ethyl acetate to affordcolorless prisms (1.5 g, 88%), m.p. 157°-158° C.

Elemental Analysis for C₂₉ H₂₉ N₃ O₆ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  67.56;        5.67;   8.15    Found:   67.43;        5.70;   8.10    ______________________________________

¹ H-NMR (200 MHz, CDCl₃) δ: 0.68(3H,t), 1.50(3H,t), 3.57(3H,s),3.81(3H,s), 3.87(2H,q), 4.67(2H,q), 5.67(2H,s), 7.04(2H,d), 7.15(1H,t),7.23-7.50(6H,m), 7.55(1H,dd), 7.72(1H,dd).

IR(KBr)cm⁻¹ : 1710, 1650, 1615, 1550, 1475, 1455, 1445, 1430, 1410,1390, 1375, 1350, 1320, 1270, 1240, 1220, 1140, 1120, 1040, 1010, 800,765, 755.

54h) Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

To methanol (15 ml) were added the compound (1.0 g) obtained in Example(54g), hydroxylamine hydrochloride (0.28 g) and MeONa (0.22 g). Themixture was heated for 6 hours under reflux. To the reaction mixture wasadded water. Resulting crystalline precipitates were collected byfiltration and recrystallized from ethyl acetate-hexane to affordcolorless prisms (0.7 g, 77%), m.p.186°-187° C.

¹ H-NMR (200 MHz, CDCl₃) δ: 1.43(3H,t), 3.46(3H,s), 4.39(2H,q),5.62(2H,s), 6.88-7.01(4H,m), 7.09(2H,d), 7.26-7.30(1H,m), 7.45(1H,dd),7.54-7.60(2H,m), 7.85-7.89(1H,m), 10.25(1H,brs).

IR(KBr)cm⁻¹ : 1780, 1720, 1610, 1550, 1490, 1470, 1435, 1410, 1390,1350, 1280, 1250, 1220, 1130, 1040, 755.

54i) Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

A mixture of the compound (0.23 g) obtained in Example (54g), methylchloroformate (66 mg) and 2,4,6-trimethylpyridine (85 mg) in toluene (1ml) was stirred for 16 hours at 80°-90° C. Precipitates were filteredoff, and the solvent was removed in vacuo. The residue was added to amixture of hydroxylamine hydrochloride (42 mg) and NaOMe (32 mg) inmethanol (2 ml). The mixture was heated for 5.5 hours under reflux. Thereaction mixture was concentrated to dryness, and the residue wasdissolved in ethyl acetate, washed with dilute hydrochloric acid anddried over MgSO₄. The solvent was evaporated in vacuo, and the residuewas crystallized from ethyl acetate-methanol to afford colorless prisms(0.13 g, 55%).

54j) 2-Ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

A mixture of the compound (0.47 g) obtained in Example (54h) and 1N NaOH(3 ml) in methanol (3 ml) was heated for 30 minutes under reflux. Thereaction mixture was adjusted to pH 3-4 with 1N HCl. Resultingcrystalline precipitates were collected by filtration and recrystallizedfrom ethyl acetate-hexane. The crystals were suspended in water (2 ml),and the suspension was stirred for 2 hours at 60° C. Insoluble materialswere collected by filtration and dried to afford colorless crystals(0.25 g, 54%). This product was in agreement with that obtained inExample 1.

¹ H-NMR (200 MHz, DMSO-d₆) δ: 1.38(3H,t), 4.58(2H,q), 5.68(2H,s)7.04(2H,d), 7.13-7.25(3H,m), 7.45-7.69(6H,m).

Example 55 2-Ethyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine

To a solution of 5,7-dimethyl-2-ethylimidazo 4,5-b!pyridine (0.7 g)synthesized in accordance with European Patent EP 0400974 A2 indimethylformamide (10 ml) was added sodium hydride (60% in oil; 0.18 g)under ice-cooling, and the mixture was stirred for 10 minutes. To theice-cooling reaction mixture was added the compound (2.10 g) obtained inExample (22c), and the mixture was stirred for 30 minutes at roomtemperature. The reaction mixture was partitioned between water andethyl acetate. The organic layer was washed with water, dried andconcentrated to dryness. The residue was purified by columnchromatography on silica gel to give a brown syrup. To a solution of theproduct in methanol (10 ml) was added an aqueous solution of 1N NaOH (2ml), and the solution was stirred for 30 minutes at room temperature.The reaction mixture was adjusted to pH 3-4 with 1N HCl and extractedwith chloroform. The extract was dried, and the solvent was removedunder reduced pressure. The residue was purified by chromatography onsilica gel. Crude crystals thus obtained was recrystallized from ethylacetate-hexane to afford the title compound as colorless crystals (0.35g, 20%), m.p.149°-152° C.

Elemental Analysis for C₂₅ H₂₃ N₅ O₂.0.1H₂ O(427.29):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  70.27;        5.47; 16.39    Found:   70.24;        5.42;   16.40    ______________________________________

¹ H-NMR (200 MHz, CDCl₃) δ: 1.24(3H,t), 2.42(3H,s), 2.51(3H,s),2.64(2H,q), 5.39(2H,s), 6.83(1H,s), 7.05(2H,d), 7.17(2H,d),7.29-7.34(1H,m), 7.48(1H,dt), 7.57(1H,dt), 7.75-7.80(1H,m).

IR(KBr)cm⁻¹ : 1780, 1610, 1595, 1505, 1495, 1465, 1455, 1425, 1390, 765.

Example 56 2-Ethyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-7-methylimidazo4,5-b!pyridine-5-carboxylic acid

56a) 4-Methyl-2-nitraminepyridine

2-Amino-4-methylpyridine (25 g) was added gradually to conc. sulfuricacid (150 ml) under ice-cooling. To the mixture was added dropwise apreviously ice-cooled mixture of conc. nitric acid (26 ml) and conc.sulfuric acid (19 ml), maintaining at 0° C. The mixture was then stirredfor 2.5 hours. The reaction mixture was poured into 300 g of ice, andthe mixture was neutralized with aqueous ammonia under ice-cooling.Insoluble materials were filtered off, and the filtrate wasconcentrated. Resulting crystalline precipitates were collected byfiltration and dried to afford the title compound as yellow needles(26.3 g, 74%), m.p.185°-187° C.

¹ H-NMR (200 MHz, DMSO-d₆) δ: 2.40(3H,s), 7.02(1H,dd), 7.47(1H,s),8.05(1H,d).

IR(KBr)cm⁻¹ : 1625, 1600, 1520, 1415, 1375, 1365, 1320, 1295, 1260,1215, 1165.

56b) 2-Amino-4-methyl-3(and 5-nitropyridine

4-Methyl-2-nitraminepyridine (34.1 g) was added to conc. sulfuric acid(170 ml), maintaining at 0° C. The mixture was stirred for 24 hours atroom temperature and poured into ice (500 g), followed by neutralizationwith aqueous ammonium hydroxide under ice-cooling. The reaction mixturewas cooled to give a crystalline product. The crystals were collected byfiltration and dried to give a mixture of 3-nitro derivative and 5-nitroderivative as yellow crystals (23,5 g, 3-nitro derivative:5-nitroderivative=1:1.7).

3-Nitro derivative: ¹ H-NMR (200 MHz,DMSO-d₆) δ: 2.36(3H,s), 6.60(1H,d),7.09(2H,brs), 8.07(1H,d).

5-Nitro derivative: ¹ H-NMR (200 MHz,DMSO-d₆) δ: 2.46(3H,s), 6.32(1H,s),7.30(2H,brs), 8.76(1H,s).

56c) 2-Ethyl-7-methylimidazo 4,5-b!pyridine

A suspension of the compound (23.4 g) obtained in Example (56b) and5%Pd--C (13 g) in methanol (500 ml) was stirred under hydrogenatmosphere. Insoluble materials were filtered off, and the filtrate wasconcentrated to dryness to give a brown syrup. The syrup was mixed inpolyphosphoric acid. (240 g) And propionic acid (40 g), and the mixturewas stirred for 20 minutes at 100° C. The reaction mixture was pouredinto ice-water and neutralized with aqueous ammonium hydroxide.Resulting crystalline precipitates were collected by filtration andrecrystallized from chloroform. Resulting crystalline precipitates(by-product) were collected by filtration. The filtrate and the motherliquor were combined and concentrated, then resulting crystallineprecipitates were collected by filtration and washed with chloroform.The filtrates were combined and concentrated to dryness, which waspurified by chromatography on silica gel. Crude crystals thus obtainedwere recrystallized form ethyl acetate-hexane afforded the titlecompound as pale yellow crystals (4.55 g), m.p.117°-119° C.

¹ H-NMR (200 MHz,CDCl₃) δ: 1.56(3H,t), 2.70(3H,s), 3.11(2H,q),7.05(1H,d), 8.19(1H,d).

IR(KBr)cm⁻¹ : 1630, 1540, 1445, 1375, 1365, 890, 820.

56d) 2-Ethyl-7-methylimidazo 4,5-b!pyridin-4N-oxide

To an ice-cooling solution of the compound (2.0 g) obtained in Example(56c) in chloroform (30 ml) was added m-chlorobenzoic acid (2.78 g). Themixture was stirred for 10 minutes and then heated for one hour underreflux. The reaction mixture was concentrated to dryness under reducedpressure. The concentrate was purified by chromatography on silica gelto give crude crystals. Recrystallization from ethyl acetate-methanolafforded the title compound as colorless needles (1.92 g, 85%),m.p.189°-191° C.

Elemental Analysis for C₉ H₁₁ N₃ O.0.2H₂ O (180.81):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  59.79;        6.36;   23.24    Found:   59.94;        6.61;   23.23    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.33(3H,t), 2.46(3H,s), 2.86(2H,q),6.96(1H,d), 8.00(1H,d).

IR(KBr)cm⁻¹ : 1480, 1420, 1280, 1250, 1230, 1170, 765.

56e) 5-Cyano-2-ethyl-7-methylimidazo 4,5-b!pyridine

To a suspension of the compound (2.0 g) obtained in Example (56d) inacetonitrile (30 ml) were added trimethylsilyl cyanide (4.5 g) andtriethylamine (1.15 g), and the mixture was heated for 16 hours underreflux. The reaction mixture was concentrated to dryness under reducedpressure. The residue was purified by chromatography on silica gel.Crude crystals thus obtained were recrystallized from ethyl acetate toafford the title compound as pale yellow needles (1.40 g, 66%),m.p.216°-218° C. (decomp.).

Elemental Analysis for C₁₀ H₁₀ N₄ (186.22):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  64.50;        5.41;   30.09    Found:   64.26;        5.45;   29.87    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.54(3H,t), 2.75(3H,s), 3.22(2H,q),7.50(1H,s).

IR(KBr)cm⁻¹ : 2225, 1615, 1600, 1515, 1415, 1395, 1375, 1295, 1270, 785.

56f) Methyl 2-ethyl-7-methylimidazo 4,5-b!pyridine-5-carboxylate

The compound (1.3 g) obtained in Example (56e) was suspended in9N-hydrogen chloride in methanol solution (30 ml). The suspension washeated for 3 hours under reflux. The reaction mixture was concentratedunder reduced pressure, and the pH was adjusted to 5 with a saturatedaqueous solution of sodium hydrogencarbonate, followed by extractionwith chloroform. The extract was dried, and the solvent was removedunder reduced pressure to give crude crystals. Recrystallization fromethyl acetate-methanol afforded the title compound as colorless prisms(1.33 g, 86%), m.p.208°-210° C.

Elemental Analysis for C₁₁ H₁₃ N₃ O₂ (219.24):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  60.26;        5.98;   19.17    Found:   60.14;        5.99;   19.07    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.41(3H,t), 2.74(3H,s), 3.14(2H,q),4.03(3H,s), 7.92(1H,s).

IR(KBr)cm⁻¹ : 3240, 1730, 1615, 1510, 1435, 1405, 1385, 1300, 1250,1200, 750.

56g) Methyl 2-ethyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-7-methylimidazo4,5-b!pyridine-5-carboxylate

To a solution of the compound (1.0 g) obtained in Example (56f) indimethylformamide (10 ml) was added sodium hydride (60% in oil; 0.21 g)at room temperatures. The mixture was stirred for 5 minutes, and to themixture was added the compound (2.27 g) obtained in Example (22c),followed by stirring for one hour at room temperatures. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with a saturated aqueous saline solution and dried. Thesolvent was removed under reduced pressure, and the residue was purifiedby chromatography on silica gel to give colorless crystals. The crystalswere dissolved in chloroform(7.5 ml)-methanol(15 ml). To the solutionwas added an aqueous solution of 1N sodium hydroxide (3.5 ml), and themixture was stirred for 20 minutes at room temperature. To the reactionmixture was added 1N-HCl to adjust the pH to 3 to 4, followed byextraction with chloroform. The extract was dried, and the solvent wasremoved under reduced pressure to give crude crystals. Recrystallizationfrom ethyl acetate-methanol afforded the title compound as colorlessprisms (1.07 g, 58%), m.p.246°-248° C. (decomp.).

Elemental Analysis for C₂₆ H₂₃ N₅ O₄ (469.50):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  66.51;        4.94;   14.92    Found:   66.37;        4.97;   14.84    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.31(3H,t), 2.63(3H,s), 2.80(2H,q),3.93(3H,s), 5.52(2H,s), 7.14(2H,d), 7.23(2H,d), 7.35(1H,dd),7.43-7.63(2H,m), 7.76(1H,dd), 7.92(1H,s), 9.15(1H,brs).

IR(KBr)cm⁻¹ : 1780, 1705, 1485, 1465, 1435, 1275, 1220, 760.

56h) 2-Ethyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-7-methylimidazo4,5-b!pyridine-5-carboxylic acid

To a suspension of the compound (0.9 g) obtained in Example (56g) inmethanol (20 ml) was added 1N aqueous solution of sodium hydroxide (4.5ml), and the mixture was stirred for 3 hours at 60° C. To the reactionmixture was added 1N HCl to adjust the pH to 3-4. Resulting crystallineprecipitates were collected by filtration and dried. Crude crystals thusobtained were recrystallized from ethyl acetate-methanol afforded thetitle compound as colorless crystals (0.61 g, 69%), m.p.261°-164° C.(decomp.).

Elemental Analysis for C₂₅ H₂₁ N₅ O₄ (455.47):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  65.93;        4.65;   15.38    Found:   65.63;        4.67;   15.15    ______________________________________

¹ H-NMR (200 MHz,DMSO-d₆) δ: 1.25(3H,t), 2.64(3H,s), 2.86(2H,q),5.62(2H,s), 7.22(2H,d), 7.29(2H,d), 7.48-7.72(4H,m), 7.88(1H,s).

IR(KBr)cm⁻¹ : 1790, 1695, 1285, 1270.

Example 57 Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

57a) Methyl 3-amino-2-2'-(ethoxycarbonyloxycarbamimidoyl)biphenyl-4-yl!methylamino!benzoate

To a suspension of the compound (7.1 g) obtained in Example (1a) inmethanol (120 ml) were added. hydroxylamine hydrochloride (5.56 g) andtriethylamine (6.06 g). The mixture was stirred for 3 days at 70° C.under nitrogen atmosphere. Methanol was removed in vacuo. The residuewas partitioned between ethyl acetate (200 ml) and water (50 ml). Theorganic layer was washed with water, dried and concentrated to drynessunder reduced pressure. To a solution of the residue in tetrahydrofuran(100 ml) was added triethylamine (2 g) under ice-cooling. To the mixturewas added dropwise a solution of ethyl chlorocarbonate (1.4 g) intetrahydrofuran (20 ml). The reaction mixture was stirred for one hourat the same temperature, and the solvent was removed in vacuo. Theresidue was partitioned between ethyl acetate-water. The organic layerwas washed with water, dried and concentrated to dryness to give a paleyellow syrup (8.6 g).

¹ H-NMR (200 MHz,CDCl₃) δ: 1.35(3H,t), 3.80(3H,s), 4.20(2H,s),4.32(2H,q), 4.57(2H,br s), 6.83-6.93(2H,m), 7.27-7.54(8H,m),7.64-7.70(1H,m).

IR(CHCl₃)cm⁻¹ : 3520, 3415, 3350, 1765, 1700, 1635.

57b) Methyl 2-ethoxy-1-2'-(ethoxycarbonyloxycarbamimidoyl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The pale brown syrup (8.58 g) obtained in Example (57a) was dissolved indioxane (20 ml). To the solution were added tetraethoxymethane (8.64 g)and acetic acid (1.56 g). The mixture was stirred for 2 hours at 100° C.The reaction mixture was concentrated to dryness. The residue wascrystallized from ethyl acetate (50 ml). Resulting crystallineprecipitates were collected by filtration to obtain the title compound.

¹ H-NMR(200 MHz,CDCl₃) δ: 1.50(3H,t), 3.77(3H,s), 4.31(2H,q),4.69(2H,q), 5.64(2H,s), 7.01(2H,d), 7.17(1H,t), 7.26-7.55(6H,m),7.72(1H,d).

IR(CHCl₃)cm⁻¹ : 3520, 3410, 1765, 1710, 1635, 1545.

57c) Methyl 2-ethoxy-1-2-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The crude crystals (4.0 g) obtained in Example (57b) was dissolved inethyl acetate (50 ml). To the solution was added 1,8-diazabicyclo5.4.0!undec-7-ene (DBU, 3.2 g), and the mixture was stirred for 2 hoursat 80° C. The reaction mixture was partitioned between ethyl acetate (50ml) and 1N HCl (20 ml). The organic layer was washed with water, driedand concentrated to dryness. The residue was crystallized fromchloroform-ethyl acetate to afford the title compound as colorlessprisms (2.1 g, 45%), which was in agreement with that obtained inExample (1d).

Example 58 Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The crude crystals (4.0 g) obtained in Example (57) were dissolved inethyl acetate (50 ml). To the solution was added potassium carbonate (3g) (in place of DBU), and the mixture was stirred for 18 hours at 90° C.Resulting crystalline precipitates were collected by filtration andsuspended in water (30 ml). The pH of the suspension was adjusted to 3-4with 2N-HCl. Resulting crystals were collected by filtration and driedto obtain the title compound as colorless crystals (1.81 g, 38%), whichwere in agreement with those obtained in Example (57).

Example 59 2-Ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl)methyl!benzimidazole-7-carboxylicacid

The compound (3.2 g) obtained according to the procedure of Example (1d)was suspended in 0.5N NaOH (50 ml). The suspension was stirred for 3hours at 60° C. The reaction mixture was adjusted to pH 3 to 4 with2N-HCl. Resulting crystals were collected by filtration and washed withwater. The crystals thus obtained were stirred in ethanol (45 ml) forone hour to afford colorless prisms (2.9 g, 94%), m.p.212°-214° C.

Elemental Analysis for C₂₅ H₂₀ N₄ O₄ :

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  65.78;        4.42;   12.27    Found:   65.72;        4.67;   12.28    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.47(3H,t), 4.67(2H,q), 5.77(2H,s),7.07-7.70(11H,m), 13.0(1H,br s)

IR(Nujol)cm⁻¹ : 1780, 1700, 1555, 1470, 1440, 1290, 1050, 765.

Example 60 Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The compound obtained in Example (1c) (0.89 g) was added totetrahydrofuran (15 ml), to which was added 1,1'-thiocarbonyldiimidazole (0.36 g) while stirring at room temperatures. After stirringfor 30 minutes, the reaction mixture was concentrated to dryness. Theconcentrate was dissolved in ethyl acetate, and the solution was washedwith dilute hydrochloric acid and water, and then dried. To a solutionof the residue in chloroform-methanol (5:1, 150 ml) was added silica gel(7 g), and the mixture was stirred for 48 hours at room temperature.Insoluble materials were filtered off, and the filtrate was concentratedto dryness to give a syrup. The product was purified by columnchromatography on silica gel to give crystals. Recrystallization fromethyl acetate afforded colorless prisms (0.33 g, 34%), m.p.211°-212° C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₄ S:

    ______________________________________           C (%) H (%)       N (%)   S (%)    ______________________________________    Calcd.:      64.18;  4.56;     11.52;                                         6.59    Found:       64.44;  4.56;     11.44;                                         6.42    ______________________________________

¹ H-NMR(90 MHz,CDCl₃) δ: 1.43(3H,t), 3.70(3H,s), 4.57(2H,q), 5.67(2H,s),6.93-7.60(10H,m), 7.77-7.90(1H,m), 9.43(1H, brs).

IR(Nujol)cm⁻¹ : 1715, 1665, 1550, 1440, 1430, 1285, 1250, 1040.

Example 61 2-Ethoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The compound (0.68 g) obtained in Example (60a) was suspended in a 0.2Naqueous solution of NaOH (10 ml). The suspension was stirred for 20hours at 60° C., and then the pH was adjusted to 3-4 with 1N-HCl.Resulting crystals were collected by filtration and recrystallized frommethanol to afford colorless prisms (0.29 g, 44%), m.p.210°-211° C.

Elemental Analysis for C₂₅ H₂₀ N₄ O₄ S:

    ______________________________________           C (%) H (%)       N (%)   S (%)    ______________________________________    Calcd.:      63.55;  4.27;     11.86;                                         6.79    Found:       63.26;  4.32;     11.84;                                         6.59    ______________________________________

¹ H-NMR (90 MHz,CDCl₃) δ: 1.49(3H,t), 4.64(2H,q), 5.76(2H,s),7.06-7.70(11H,m), 12.13(1H,brs).

IR(Nujol)cm⁻¹ : 1720, 1670, 1550, 1425, 1280, 1035.

Working Example 62 Methyl 2-ethoxy-1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-ylbiphenyl-4-yl!methyl!benzimidazole-7-carboxylate

A mixture of methyl 2-ethoxy-1-(2'-hydroxycarbamimidoyl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate(0.66 g) obtained in Working Example (1c), thiocarbonyldiimidazole (0.3g) and 1,5-diazabicyclo 4.3.0!non-5-ene (0.56 g) in acetonitrile (15 ml)was stirred at room temperature for 20 hours. After evaporation of thesolvent, the residue was dissolved in water and the pH of the solutionwas adjusted to pH 4-5, followed by extraction with ethylacetate. Theextract was dried and concentrated to dryness and the residue waspurified by silica gel column chromatography to give crystals.Recrystallization from ethyl acetate-MeOH gave colorless crystals (0.2g, 20%).

¹ H-NMR (200 MHz,DMSO-d₆) δ: 1.41(3H,t), 3.68(3H,s), 4.61(2H,q),5.49(2H,s), 6.89(2H,d), 7.15(2H,d), 7.18(1H,t), 7.25-7.61(5H,m),7.68(1H,dd), 8.81(1H,s)

Working Example 63 Methyl 2-butyl-1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazol-7-carboxylate

63a) Methyl 1-2'-(N-acetoxycarbamimidoyl)biphenyl-4-yl!methyl!-2-butylbenzimidazole-7-carboxylate

To a solution of methyl 2-butyl-1-2'-(hydroxycarbamimidoyl)biphenyl-4-yl!methyl!bezimidazole-7-carboxylate(1.83 g) in dichloromethane (20 ml) was added triethylamine (0.46 g) andacetic anhydride (0.46 g), and the reaction mixture was stirred at roomtemperature for 2 hours. After evaporation of the solvent, the residuewas partitioned between ethylacetate and water and the organic layer waswashed with an aqueous solution of NaHCO₃ and water. The solution wasdried and concentrated to dryness to give a pale yellow solid (1.99 g,quant.)

¹ H-NMR (200 MHz,CDCl₃) δ: 0.96(3H,t), 1.38-1.56(2H,m), 1.80-1.95(2H,m),2.14(3H,s), 2.93(2H,t), 3.74(3H,s), 4.60(2H,brs), 5.76(2H,s),6.87(2H,d), 7.20-7.50(6H,m), 7.55-7.65(2H,m), 7.93(1H,d)

IR(Nujol)cm⁻¹ : 3325, 3170, 1750, 1720, 1630, 1280

This compound was used to the next reaction without any purification.

63b) Methyl 2-butyl-1-2'-(2.5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazol-7-carboxylate

To a mixture of methyl 2-butyl-1-2'-(acetoxycarbamimidoyl)biphenyl-4-yl)methyl!benzimidazole-7-carboxylate(2.0 g) and CS₂ (1.5 g) in DMF (12 ml) was added sodium hydride (60% inoil, 0.56 g) during a period of 10 minutes and the reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto ice-water and the pH of the solution was adjusted to 3. The mixturewas extracted with ethylacetate and the extract was washed with water,dried, and concentrated to dryness. The residue was crystallized fromchloroform-methanol to afford pale yellow prisms (0.64 g, 32%).

m.p. 180°-181° C.

Elemental Analysis for C₂₈ H₂₆ N₄ O₃ S:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  67.45;        5.26;   11.24    Found:   67.14;        5.05;   10.97    ______________________________________

¹ H-NMR (200 MHz,DMSO-d₆) δ: 0.90(3H,t), 1.30-1.50 (2H,m),1.69-1.84(2H,m), 2.90(2H,t), 3.65(3H,S), 5.73(2H,S), 6.89 (2H,d), 7.19(2H,d), 7.28(1H,t), 7.44-7.72(5H,m), 7.87(2H,d)

IR(Nujol)cm⁻¹ : 1720, 1430, 1285, 1265, 755.

Working Example 64 2-Butyl-1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

A solution of methyl ester (0.42 g) obtained in Working Example 63 in anaqueous solution of 0.3N NaOH (8.2 ml) was stirred at 50° C. for 1.5hours. The pH of the reaction solution was adjusted to 3 with 2N HCl andthe solution was extracted with ethylacetate (40 ml). The organic layerwas washed with water and concentrated to dryness. The resultingcrystals were recrystallized from ethanol-ethylacetate to affordcolorless prisms (0.25 g, 61%).

m.p. 178°-180° C.

Elemental Analysis for C₂₇ H₂₄ N₄ O₃ S:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  66.92;        4.99;   11.56    Found:   66.72;        4.95;   11.72    ______________________________________

¹ H-NMR (200 MHz,DMSO-d₆) δ: 0.88(3H,t), 1.28-1.47(2H,m),1.65-1.80(2H,m), 2.85(2H,t), 5.90(2H,S), 6,90(2H,d), 7.17(2H,d),7.26(1H,t), 7.42-7.69(5H,m), 7.85(1H,d).

IR(Nujol)cm⁻¹ : 3400, 1700, 1430, 1410, 1335, 1230.

Working Example 65 Methyl 2-butyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl!biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The tile compound (0.22 g) was prepared in 44% yield according to theprocedure described in Working Example 60 from the hydroxycarbamimidoylderivative (0.46 g) obtained in Working Example 2.

m.p. 178°-179° C.

Elemental Analysis for C₂₈ H₂₆ N₄ O₃ S:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  67.45;        5.26;   11.24    Found:   67.31;        5.27;   11.25    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 0.92(3H,t), 1.30-1;50(2H,m), 1.60-1.73(2H,m),3.62(3H,s), 5.69(2H,s), 6.72(2H,d), 6.98-7.27(5H,m), 7.53-7.80(3H,m),7.80-7.89(1H,m), 11.35(1H,brs)

IR(Nujol)cm⁻¹ : 1720, 1700, 1660, 1435, 1290, 1280, 1265, 1125, 760, 750

Working Example 66 2-Butyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl!biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

The title compound (0.16 g) was prepared in 82% yield according to theprocedure for Working Example 61 from the compound (0.2 g) obtained inWorking Example 65.

m.p. 238°-239° C. (dec)

Elemental Analysis for C₂₇ H₂₄ N₄ O₃ S.1/3H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  66.11;        5.07;   11.42    Found:   66.29;        4.98;   11.58    ______________________________________

¹ H-NMR (200 MHz,DMSO-d₆) δ: 0.88(3H,t), 1.27-1.45(2H,m),1.65-1.80(2H,m), 2.83(2H,t), 5.88(2H,s), 6.87(2H,s), 7.14(2H,d),7.24(1H,t), 7.41-7.64(5H,m), 7.83(2H,d)

IR(Nujol)cm⁻¹ : 3255, 1675, 1450, 1420, 1240, 1230, 1205, 755

Working Example 67 Methyl 2-ethyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl!biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The title compound (0.17 g) was prepared in 38% yield according to theprocedure for Working Example 60 from the compound (0.4 g) obtained inWorking Example 31.

m.p. 203°-205° C.

Elemental Analysis for C₂₆ H₂₂ N₄ O₃ S.0.5H₂ O:

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  65.12;        4.83;   11.68    Found:   65.30         4.54;   11.63;    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.13(3H,t), 2.64(2H,q), 3.53(3H,s),5.62(2H,s), 6.59(2H,d), 6.8-7.9(7H,m)

IR(KBr)cm⁻¹ : 1715, 1690, 1600, 1520

Working Example 68 2-Ethyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl!biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid

The title compound (0.4 g) was prepared in 58% yield according to theprocedure for Working Example 61 from the ester (0.7 g) obtained inWorking Example 67.

¹ H-NMR (200 MHz,DMSO-d₆) δ: 1.30(3H,t), 2.86(2H,q), 5.89(2H,s),6.90(2H,d), 7.15(2H,d), 7.27(1H,t), 7.4-7.7(5H,m), 7.86(1H,d)

IR(KBr)cm⁻¹ : 1700, 1655, 1570

Working Example 69 Methyl 2-ethyl-1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate

The title compound (0.12 g) was prepared in 22% yield) according to theprocedure for Working Example 62 from the compound (0.45 g) obtained inWorking Example 31.

¹ H-NMR (200 MHz,CDCl₃) δ: 1.23(3H,t), 2.78(2H,q), 3.76(3H,s),5.52(2H,s), 6.91(2H,d), 7.10(2H,d), 7.1-7.7(6H,m), 7.93(1H,d)

Working Example 70 Methyl 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylbenzimidazole-7-carboxylate

70a) Methyl 1-2'-(N-acetoxycarbamimidoyl)biphenyl-4-yl!methyl!2-propylbenzimidazole-7-carboxylate

The title compound (0.95 g) was prepared in 86% yield according to theprocedure described in Working Example 63 from the hydrocarbamimidoylderivative (1 g) obtained in Working Example 30.

m.p. 177°-178° C.

Elemental Analysis for C₂₈ H₂₈ N₄ O₄ S.0.1H₂ O (486.36):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  69.15;        5.84;   11.52    Found:   68.93;        5.80;   11.54;    ______________________________________

¹ H-NMR (200 MHz,CDCl₃) δ: 1.07(3H,t), 1.84-2.03(2H,m), 2.15(3H,s),2.91(2H,t), 3.74(3H,s), 4.57(2H,brs), 5.76(2H,s), 6.87(2H,d),7.21-7.52(6H,m), 7.59-7.64(2H,m), 7.94(1H,dd)

IR(KBr)cm⁻¹ : 3495, 3365, 1745, 1720, 1620, 1285, 1275, 1260, 1230, 1205

70b) Methyl 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxodiazol-3-yl)biphenyl-4-yl!methyl!-2-propylbenzimidazole-7-carboxylate

The title compound (0.14 g) was prepared in 28% yield according to theprocedure described in Working Example (63b) from theN-acetoxycarbamimidoyl derivative (0.5 g) obtained in Working Example(70a).

m.p. 206°-209° C. (decomp.)

Elemental Analysis for C₂₇ H₂₄ N₄ O₃ S.0.2H₂ O (488.18):

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  66.43;        5.04;   11.48    Found:   66.42;        5.14;   11.51    ______________________________________

¹ H-NMR (200 MHz,DMSO-d₆) δ: 0.98(3H,t), 1.71-1.90(2H,m), 2.88(2H,t),3.65(3H,s), 5.73(2H,s), 6.89(2H,d), 7.21(2H,d), 7.28(1H,t),7.44-7.72(5H,m), 7.88(1H,dd)

IR(KBr)cm⁻¹ : 1725, 1450, 1435, 1410, 1335, 1325, 1285, 1270, 1210,1125, 770, 760

Working Example 71 Methyl 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylbenzimidazole-7-carboxylate

The title compound (0.16 g) was prepared in 25% yield according to theprocedure described in Working Example 60 from the hydroxycarbamimidoylderivative (0.58 g) obtained in Working Example 30.

m.p. 225°-227° C. (decomp.)

Elemental Analysis for C₂₇ H₂₄ N₄ O₃ S.0.2H₂ O

    ______________________________________           C (%)       H (%)   N (%)    ______________________________________    Calcd.:  66.43;        5.04;   11.48    Found:   66.64;        5.16;   11.26    ______________________________________

¹ H-NMR(200 MHz, CDCl₃) δ: 1.01(3H,t), 1.60-1.80(2H,m), 2.70(3H,t),3.60(3H,s), 5.69(3H,s), 6,71(2H,d), 6.96-7.05(4H,m), 7.22-7.26(1H,m)7.50-7.59(3H,m), 7.83-7.87(1H,m), 11.40(1H,brs)

IR(KBr)cm⁻¹ : 1720, 1700, 1685, 1460, 1435, 1410, 1290, 1270, 1125, 755.

The following compounds are prepared according to the proceduresdescribed in Working Examples 1-71.

Working Example 72 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxybenzimidazole-7-carboxylicacid Working Example 73 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-propoxybenzimidazole-7-carboxylicacid Working Example 74 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-isopropoxybenzimidazole-7-carboxylicacid Working Example 75 2-butoxy-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid Working Example 76 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylthiobenzimidazole-7-carboxylicacid Working Example 77 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylthiobenzimidazole-7-carboxylicacid Working Example 78 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylthiobenzimidazole-7-carboxylicacid Working Example 79 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-isopropylthiobenzimidazole-7-carboxylicacid Working Example 80 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylaminobenzimidazole-7-carboxylicacid Working Example 81 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylaminobenzimidazole-7-carboxylicacid Working Example 82 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylaminobenzimidazole-7-carboxylicacid Working Example 83 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylbenzimidazole-7-carboxylicacid Working Example 84 2-cyclopropyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid Working Example 85 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2,4-dimethylthieno3,4-d!imidazole-6-carboxylic acid Working Example 86 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethyl-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 87 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-propylthieno3,4-d!imidazole-6-carboxylic acid Working Example 88 2-cyclopropyl-1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 89 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 90 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 91 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-propoxythieno3,4-d!imidazole-6-carboxylic acid Working Example 92 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-methylthiothieno3,4-d!imidazole-6-carboxylic acid Working Example 93 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 94 1- 2'-2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-methylaminothieno3,4-d!imidazole-6-carboxylic acid Working Example 95 1-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylamino-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 96 1- 2'-2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxybenzimidazole-7-carboxylicacid Working Example 97 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!2-propoxybenzimidazole-7-carboxylicacid Working Example 98 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-isopropoxybenzimidazole-7-carboxylicacid Working Example 99 2-butoxy-1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid Working Example 100 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylthiobenzimidazole-7-carboxylicacid Working Example 101 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylthiobenzimidazole-7-carboxylicacid Working Example 102 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylthiobenzimidazole-7-carboxylicacid Working Example 103 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-isopropylthiobenzimidazole-7-carboxylicacid Working Example 104 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylaminobenzimidazole-7-carboxylicacid Working Example 105 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylaminobenzimidazole-7-carboxylicacid Working Example 106 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-propylaminobenzimidazole-7-carboxylicacid Working Example 107 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methylbenzimidazole-7-carboxylicacid Working Example 108 2-cyclopropyl-1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid Working Example 109 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2,4-dimethylthieno3,4-d!imidazole-6-carboxylic acid Working Example 110 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethyl-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 111 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-propylthieno3,4-d!imidazole-6-carboxylic acid Working Example 112 2-cyclopropyl-1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 113 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 114 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 115 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-propoxythieno3,4-d!imidazole-6-carboxylic acid Working Example 116 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-methylthiothieno3,4-d!imidazole-6-carboxylic acid Working Example 117 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 118 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-4-methyl-2-methylaminothieno3,4-d!imidazole-6-carboxylic acid Working Example 119 1-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylamino-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 120 1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxybenzimidazole-7-carboxylicacid Working Example 121 1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethoxybenzimidazole-7-carboxylicacid Working Example 122 2-butyl-1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylicacid Working Example 123 1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylthiobenzimidazole-7-carboxylicacid Working Example 124 1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-methoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 125 1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethoxy-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 126 2-butyl-1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 127 1-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-2-ethylthio-4-methylthieno3,4-d!imidazole-6-carboxylic acid Working Example 128 2-ethyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 129 2-propyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 130 2-butyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 131 2-methoxy-3-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 132 2-ethoxy-3-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 133 2-propoxy-3-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 134 2-cyclopropyl-3-2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 135 2-ethyl-3-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 136 2-propyl-3-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 137 2-butyl-3-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 138 2-methoxy-3-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 139 2-ethoxy-3-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 140 2-propoxy-3-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 141 2-cyclopropyl-3-2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 142 2-methyl-3-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 143 2-ethyl-3-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 144 2-cyclopropyl-3-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Working Example 145 2-ethoxy-3-2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazol-3-yl)biphenyl-4-yl!methyl!-5,7-dimethylimidazo4,5-b!pyridine Experimental Example 1

Inhibitory Effect of Binding of Angiotensin-II to Angiotensin Receptor

Method!

An experiment of inhibition on the binding of angiotensin II (A-II)receptor was conducted by modifying the method of Douglas et al.Endocrinology, 102, 685-696 (1978)!. An A-II receptor membrane fractionwas prepared from bovine adrenal cortex.

The compound of the present invention (10⁻⁶ M or 10⁻⁷ M and ¹²⁵I-angiotensin II (¹²⁵ I-AII) (1.85 kBq/50 microliter) were added to thereceptor membrane fraction, and the mixture was incubated at roomtemperature for one hour. The receptor-bound and free ¹²⁵ I-AII wereseparated through a filter (Whatman GF/B filter), and the radioactivityof ¹²⁵ I-AII bound to the receptor was determined.

Results!

The results relating to the compounds of the present invention are shownin Table 1!.

Experimental Example 2

Inhibitory Effect of the Compound of the Present Invention on PressorAction of AII

Method!

Jcl: SD rat (9 week old, male) were employed. On the day prior to theexperiment, these animals were applied with cannulation into the femoralartery and vein under anesthesia with pentobarbital Na. These animalswere fasted but allowed to free access to drinking water until theexperiment was started. Just on the day of conducting the experiment,the artery cannula was connected with a blood-pressure transducer, andthe average blood pressure was recorded by means of polygraph. Beforeadministration of the drug, the pressor action due to intravenousadministration of A-II (100 ng/kg) as the control was determined. Thedrugs were orally administered, then, at each point of thedetermination, A-II was administered intravenously, and the pressoraction was similarly determined. By comparing the pressor action beforeand after administration of the drug, the percent inhibition by the drugon A-II-induced pressor action was evaluated.

Results!

The results relating to the compounds of the present invention are shownin Table I!.

                                      TABLE 1    __________________________________________________________________________                             Radioreceptor                                    Pressor Response    Example                  assay  to A II (p.o.)    No.  Chemical Formula    % inhibition                                    1 mg/kg                                        3 mg/kg    __________________________________________________________________________     1          ##STR57##          79(10.sup.-6 M) 34(10.sup.-7 M)                                    +++ +++.sup.a)     3          ##STR58##          75(10.sup.-6 M) 33(10.sup.-7 M)                                        +++     9          ##STR59##          55(10.sup.-6 M) 19(10.sup.-7 M)                                    +++ +++     4          ##STR60##          44(10.sup.-6 M) 17(10.sup.-7 M)                                    +++     8          ##STR61##          40(10.sup.-6 M)  8(10.sup.-7 M)                                    +++    10          ##STR62##          51(10.sup.-6 M) 17(10.sup.-7 M)                                    +++    11          ##STR63##          41(10.sup.-6 M) 10(10.sup.-7 M)                                    +++    12          ##STR64##          78(10.sup.-6 M) 46(10.sup.-7 M)                                    +    13          ##STR65##          69(10.sup.-6 M) 31(10.sup.-7 M)                                    +++    30          ##STR66##          77(10.sup.-6 M) 35(10.sup.-7 M)                                    +++    31          ##STR67##          79(10.sup.-6 M) 41(10.sup.-7 M)                                    +++    32c          ##STR68##          79(10.sup.-6 M) 40(10.sup.-7 M)                                    +++    32          ##STR69##          75(10.sup.-6 M) 27(10.sup.-7 M)                                    +++    33          ##STR70##          70(10.sup.-6 M) 23(10.sup.-7 M)                                    ++    35          ##STR71##          79(10.sup.-6 M) 38(10.sup.-7 M)                                    +++    36          ##STR72##          60(10.sup.-6 M) 18(10.sup.-7 M)                                    +++    56          ##STR73##          94(10.sup.-6 M) 80(10.sup.-7 M)                                    +++    60          ##STR74##          84(10.sup.-6 M) 43(10.sup.-7 M)                                    +++    __________________________________________________________________________     .sup.a) +++ ≧ 70% > ++ ≧ 50% > +-

What is claimed is:
 1. A compound of the formula: ##STR75## wherein R¹is an optionally substituted hydrocarbon residue which is optionallybonded through a heteroatom; R² is selected from the group consisting of##STR76## wherein g is i) --CH₂ --, ii) --NR⁹ --, wherein R⁹ is hydrogenor lower (C₁₋₄) alkyl, iii) --O-- or iv) --S(O)_(m) -- wherein m is aninteger of 0 to 2, and >═Z and >═Z' and >═Z" are independently acarbonyl group, a thiocarbonyl group, or an optionally oxidized sulfuratom; X is a direct bond or a spacer having an atomic length of two orless between the ring Y and the ring W; W and Y are independently anoptionally substituted aromatic hydrocarbon residue optionallycontaining a hetero atom or an optionally substituted heterocyclicresidue; n is an integer of 1 or 2; and the group of the formula:##STR77## is a group selected from the class consisting of ##STR78##wherein h is >CH₂, >C═O, >C═S, >S--(O)_(m), wherein m is an integer of0-2, --NR⁹ --, wherein R⁹ is hydrogen or lower (C₁₋₄) alkyl) or --O--;and the group of the formula: ##STR79## may be optionally substituted,in addition to the group R¹ and, when (a) is an optionally substitutedcarbon atom, R¹ and (a) may optionally be bonded to each other to form aring group of a formula selected from the group consisting of ##STR80##wherein R^(1a) stands for an optionally substituted hydrocarbon residueand h" stands for --O-- or --S--" or a salt thereof.
 2. A compoundaccording to claim 1, wherein R¹, is alkyl, alkenyl, alkynyl orcycloalkyl which may be bound through a group of the formula: --N(R⁹)--,wherein R⁹ is hydrogen or lower (C₁₋₄) alkyl, --O-- or --S(O)_(m) --,wherein m is an integer of 0 to 2, and wherein R¹ may be substitutedwith hydroxy, optionally substituted amino, halogen, lower (C₁₋₄) alkoxyor lower (C₁₋₄) alkylthio.
 3. A compound according to claim 1, whereinR¹ is aryl or aralkyl which may be bound through a group of the formula:--N(R⁹)--, wherein R⁹ is hydrogen or lower (C₁₋₄) alkyl, --O-- or--S(O)_(m) --, wherein m is an integer of 0 to 2, and wherein R¹ may besubstituted with halogen, nitro, optionally substituted amino, lower(C₁₋₄) alkoxy, lower (C₁₋₄) alkylthio or lower (C₁₋₄) alkyl.
 4. Acompound according to claim 1, wherein R¹ is lower (C₁₋₈) alkyl or lower(C₂₋₈) alkenyl which may be bound through a group of the formula:--N(R⁹)--, wherein R⁹ is hydrogen or lower (C₁₋₄) alkyl, --O-- or--S(O)_(m) --, wherein m is an integer of 0 to 2, and wherein R¹ may besubstituted with hydroxy, amino, N-lower (C₁₋₄) alkylamino, N,N-dilower(C₁₋₄) alkyamino, halogen, lower (C₁₋₄) alkoxy or lower (C₁₋₄)alkylthio.
 5. A compound according to claim 1, wherein R¹ is lower(C₁₋₅) alkyl or lower (C₂₋₅) alkenyl which may be bound through a groupof the formula: --N(R⁹)--, wherein R⁹ is hydrogen or lower (C₁₋₄) alkyl,--O-- or --S(O)_(m) --, wherein m is an integer of 0 to 2, and whereinR¹ may be substituted with hydroxy, amino, halogen or lower (C₁₋₄)alkoxy.
 6. A compound according to claim 1, wherein R² is a group of theformula: ##STR81## wherein i is --O-- or --S-- and j is carbonyl group,thiocarbonyl group or an optionally oxidized sulfur atom.
 7. A compoundaccording to claim 1, wherein R² is2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group.
 8. A compound according toclaim 1, wherein R² is 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl group. 9.A compound according to claim 1, wherein R² is2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl group.
 10. A compoundaccording to claim 1, wherein W and Y are independently phenyl, pyridyl,pyrimidinyl, pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,isothiazolyl, isooxazolyl, benzofuranyl, isobenzofuranyl, indolizinyl,isoindolyl, 3-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl or pterdinyl, which may be substituted withhalogen, nitro, cyano, lower (C₁₋₄) alkoxy or optionally substitutedamino.
 11. A compound according to claim 1, wherein W is a phenylenegroup.
 12. A compound according to claim 1, wherein Y is a phenyl group.13. A compound according to claim 1, wherein X is a direct bond, lower(C₁₋₄) alkylene, --CO--, --O--, --S--, --NH--, --CO--NH--, --O--CH₂ --,--S--CH₂ -- or --CH═CH--.
 14. A compound according to claim 1, wherein Xis a direct bond.
 15. A compound according to claim 1, wherein n is aninteger of
 1. 16. A compound according to claim 1, wherein the group ofthe formula: ##STR82## in which R is the group of the formula: ##STR83##is selected from the group consisting of ##STR84## wherein R³ is a groupcapable of forming an anion.
 17. A compound according to claim 16,wherein R³ is an optionally esterified or amidated carboxyl, tetrazolyl,trifluoromethanesulfonic amide, phosphoric acid or sulfonic acid, whichmay be protected with an optionally substituted lower alkyl or acyl. 18.A compound according to claim 17, wherein R³ is a group of the formula:--CO--D, wherein D is hydroxy, an optionally substituted amino or anoptionally substituted alkoxy.
 19. A compound according to claim 18,wherein the optionally substituted alkoxy is lower (C₁₋₆) alkoxy whosealkyl moiety may be substituted by hydroxy, optionally substitutedamino, halogen, lower (C₁₋₆) alkoxy, lower (C₁₋₆) alkylthio oroptionally substituted dioxolenyl, or a group of the formula:--O--CH(R⁴)--OCOR⁵ wherein R⁴ is hydrogen, lower (C₁₋₆) alkyl, lower(C₂₋₆) alkenyl or lower (C₃₋₈) cycloalkyl; and R⁵ is lower (C₁₋₆) alkyl,lower (C₂₋₆) alkenyl, lower (C₃₋₈) cycloalkyl, lower (C₁₋₃) alkylsubstituted with lower (C₃₋₈) cycloalkyl or aryl, lower (C₂₋₃) alkenyloptionally substituted with lower (C₃₋₈) cycloalkyl or aryl, aryl, lower(C₁₋₆) alkoxy, lower (C₂₋₈) alkenyloxy, lower (C₃₋₈) cycloalkyloxy,lower (C₁₋₃) alkoxy substituted with lower (C₃₋₈) cycloalkyl or aryl,lower (C₂₋₃) alkenyloxy substituted with lower (C₃₋₈) cycloalkyl oraryl, or aryloxy.
 20. A compound according to claim 18, wherein R³ is anoptionally esterified carboxy.
 21. A pharmaceutical composition forantagonizing angiotensin II which comprises a therapeutically effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof in admixture with a pharmaceutically acceptablecarrier, excipient or diluent.
 22. A method for antagonizing angiotensinII in a mammal which comprises administering to said mammal, atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 23. A compound according toclaim 1, which is ethyl2-ethyl-4,7-dihydro-7((2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-4-oxothieno(2,3-b)pyridine-5-carboxylate.24. A compound according to claim 1, which is3-((2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-2-propyl-4(3H)-quinazolinone.25. A compound according to claim 1, which is5-butyl-3-ethyoxycarbonyl-1-((2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methylpyrazole.26. A compound according to claim 1, which is2-butyl-4-chloro-1-(2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl!methyl)imidazole-5-carboxylicacid.
 27. A compound according to claim 1, which is1-((2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-6-propoxy-3-propyluracil.28. A compound according to claim 1, wherein the group of the formula:##STR85## may be optionally substituted, in addition to R¹, with asubstituent selected from the group consisting of halogen, nitro, cyano,an optionally substituted amino group, groups represented by the formula--U--R⁶, wherein U stands for a bond, --O--, --S-- or --CO--, and R⁶stands for hydrogen or an optionally substituted lower alkyl group,groups represented by the formula --(CH₂)₁ --CO-- D', wherein D' standsfor hydrogen, hydroxyl group, optionally substituted amino, oroptionally substituted alkoxy or groups represented by the formula--OCH(R⁷)OCOR⁸, wherein R⁷ stands for hydrogen, 1-6C straight-chain orbranched lower alkyl group or a 5-7C cycloalkyl group, and R⁸ stands fora 1-6C straight-chain or branched lower alkyl group, a 2-8C loweralkenyl group, a 5-7C cycloalkyl group, a 1-3C lower alkyl groupsubstituted with a 5-7 cycloalkyl group or an aryl group, a 2-3C loweralkenyl group substituted with 5-7C cycloalkyl or an aryl group, anoptionally substituted aryl group, a 1-6C straight-chain or branchedlower alkoxy group, a 2-8C straight-chain or branched lower alkenyloxygroup, a 5-7C cycloalkyloxy group, a 1-3C lower alkoxy group substitutedwith 5-7C cycloalkyl or an aryl group, a 2-3C alkenyloxy groupsubstituted with 5-7C cycloalkyl or an optionally substituted arylgroup, or an aryloxy group, and 1 denotes 0 or 1; and tetrazolyl,trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid,each optionally protected with alkyl or acyl,wherein one or more ofthese substituents may optionally be substituted simultaneously onoptional positions of the ring.
 29. A compound according to claim 1,wherein R¹ and (a) are not bonded to each other to form said ring group.30. A compound of the formula: ##STR86## wherein the group of theformula: ##STR87## is a group selected from the class consisting of##STR88## which may be optionally substituted, in addition to the groupR¹ and R³,R² is a group of the formula: ##STR89## wherein i is --O-- or--S-- and j is >C═O, >C═S or >S(O)m, wherein m is an integer of 0 to 2,or R² is hydroxyiminocarboxamide; R¹ is lower (C₁₋₅) alkyl which may bebound through --O--, --NH-- or --S-- and which may be substituted withhydroxy, amino, N-lower (C₁₋₄) alkylamino, N,N-di-lower (C₁₋₄)alkylamino, halogen, lower (C₁₋₄) alkoxy or lower (C₁₋₄) alkylthio; andR³ is a group of the formula: --CO--D" wherein D" is hydroxy, amino,N-lower (C₁₋₄) alkylamino, N,N-di-lower (C₁₋₄) alkylamino or lower(C₁₋₄) alkoxy whose alkyl moiety may be substituted by hydroxy, amino,halogen, lower (C₂₋₆) alkanoyloxy, 1-lower (C₁₋₆) alkoxycarbonyloxy orlower (C₁₋₄) alkoxy, or tetrazolyl optionally protected with lower(C₁₋₄) alkyl or acyl; or a pharmaceutically acceptable salt thereof. 31.A compound according to claim 30, wherein R² is hydroxyiminocarboxamide.32. A compound according to claim 30, wherein R² is other than saidhydroxyiminocarboxamide.
 33. A compound according to claim 30, whereinR¹ is (C₂₋₄) alkyl which may be bound through --O--, --NH-- or --S--.34. A compound according to claim 30, wherein R³ is an optionallyesterified carboxy.